U.S. patent application number 14/240636 was filed with the patent office on 2015-10-15 for hepatitis c inhibitor compounds.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. The applicant listed for this patent is BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Megan Bertrand-Laperle, Christian Brochu, Chantal Grand-Maitre, Marc-Andre Joly, Cyrille Kuhn, Marc Pesant.
Application Number | 20150291592 14/240636 |
Document ID | / |
Family ID | 47745822 |
Filed Date | 2015-10-15 |
United States Patent
Application |
20150291592 |
Kind Code |
A1 |
Brochu; Christian ; et
al. |
October 15, 2015 |
HEPATITIS C INHIBITOR COMPOUNDS
Abstract
Compounds of Formula (I) wherein n, X.sup.1, X.sup.2, R.sup.1,
R.sup.2, Y.sup.1, Y.sup.2 and R.sup.A are defined herein, are
useful for the treatment of hepatitis C viral infection.
##STR00001##
Inventors: |
Brochu; Christian;
(Blainville, CA) ; Grand-Maitre; Chantal; (Laval,
CA) ; Joly; Marc-Andre; (Terrebonne, CA) ;
Kuhn; Cyrille; (Ridgefield, CT) ; Bertrand-Laperle;
Megan; (Laval, CA) ; Pesant; Marc; (Laval,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BOEHRINGER INGELHEIM INTERNATIONAL GMBH |
Ingelheim |
|
DE |
|
|
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
47745822 |
Appl. No.: |
14/240636 |
Filed: |
August 22, 2012 |
PCT Filed: |
August 22, 2012 |
PCT NO: |
PCT/CA2012/050577 |
371 Date: |
June 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61526942 |
Aug 24, 2011 |
|
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|
Current U.S.
Class: |
514/210.18 ;
514/210.21; 514/255.05; 514/318; 514/338; 514/364; 514/383;
514/406; 544/405; 546/194; 546/275.7; 548/143; 548/266.4;
548/358.5 |
Current CPC
Class: |
A61K 31/4196 20130101;
A61K 31/4245 20130101; A61K 31/497 20130101; A61P 31/12 20180101;
A61K 31/4545 20130101; C07D 487/04 20130101; A61P 31/14 20180101;
A61K 31/4439 20130101; C07D 513/04 20130101; A61K 31/4162
20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61K 31/4162 20060101 A61K031/4162; A61K 31/4545
20060101 A61K031/4545; A61K 31/4245 20060101 A61K031/4245; A61K
31/4196 20060101 A61K031/4196; A61K 31/4439 20060101 A61K031/4439;
A61K 31/497 20060101 A61K031/497 |
Claims
1. A compound of Formula (I) or salt thereof: ##STR00279## wherein:
X.sup.1 and X.sup.2 are each independently CR.sup.B or N; R.sup.B
is H, (C.sub.1-6)alkyl, (C.sub.1-6)haloalkyl, halo,
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; Y.sup.1 and Y.sup.2 are linked to form a
heteroaryl or heterocyclyl ring wherein each said heterocyclyl and
heteroaryl is optionally substituted 1 to 2 times with R.sup.B; - -
- is a single or double bond; R.sup.1 and R.sup.2 are each
independently (C.sub.1-6)alkyl optionally mono- or di-substituted
with --O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; or R.sup.1 and R.sup.2, together with
the carbon to which they are attached, are linked to form a
(C.sub.3-7)cycloalkyl group or a 3- to 7-membered heterocyclyl,
wherein said cycloalkyl and heterocyclyl are each optionally mono-
or di-substituted with (C.sub.1-6)alkyl; R.sup.A is
--C(.dbd.O)N(R.sup.3)(R.sup.4), --C(.dbd.O)O(R.sup.4), heterocyclyl
or heteroaryl, wherein each said heterocyclyl and heteroaryl is
optionally substituted 1 to 3 times with R.sup.41; R.sup.3 is H or
(C.sub.1-6)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl,
N((C.sub.1-6)alkyl).sub.2, --C(.dbd.O)--(C.sub.1-6)alkyl,
--SO.sub.2NH.sub.2, --SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl or
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2; R.sup.4 is H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-aryl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl or heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted 1 to 3
times with R.sup.41; or R.sup.3 and R.sup.4, together with the N
atom to which they are attached, are linked to form a heterocyclyl
or heteroaryl, wherein said heterocyclyl and heteroaryl are each
optionally substituted 1 to 3 times with R.sup.41; R.sup.41 is each
independently selected from the group consisting of halo, oxo,
cyano, nitro, R.sup.42, --C(.dbd.O)--R.sup.42,
--C(.dbd.O)OR.sup.42, --OR.sup.42, --SR.sup.42, --SOR.sup.42,
--SO.sub.2R.sup.42, --N(R.sup.43)R.sup.42,
--C(.dbd.O)--N(R.sup.43)R.sup.42, --N(R.sup.43)--C(.dbd.O)R.sup.42,
--O--C(.dbd.O)--N(R.sup.43)R.sup.42 and
--SO.sub.2--N(R.sup.43)R.sup.42; R.sup.42 is each independently
selected from the group consisting of H, (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-aryl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl and heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted with 1
to 3 substituents each independently selected from the group
consisting of: halo, cyano, OH, --COON, --O--(C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2N H.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl; R.sup.43
is H or (C.sub.1-6)alkyl; and n is 0, 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein X.sup.1 is CH and X.sup.2 is CH.
3. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y.sup.1 and Y.sup.2 are linked to
form a 5- or 6-membered heteroaryl ring optionally substituted 1 to
2 times with (C.sub.1-6)alkyl, --O--(C.sub.1-6)alkyl, NH.sub.2,
NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; and - - - is a
single or double bond.
4. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 and R.sup.2 are each
CH.sub.3; or R.sup.1 and R.sup.2 and the carbon to which they are
attached are linked to form a (C.sub.3-4)cycloalkyl group
optionally mono-substituted with (C.sub.1-3)alkyl.
5. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.A is
--C(.dbd.O)N(R.sup.3)(R.sup.4).
6. The compound according to claim 5, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is H or (C.sub.1-6)alkyl
and R.sup.4 is heterocyclyl, optionally mono- or di-substituted
with R.sup.41, R.sup.41 is each independently selected from the
group consisting of R.sup.42, --C(.dbd.O)--R.sup.42 and
--SO.sub.2R.sup.42; R.sup.42 is each independently selected from
the group consisting of (C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl.
7. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein n is 1.
8. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, having a formula ##STR00280## wherein:
R.sup.1 and R.sup.2 are each independently (C.sub.1-6)alkyl
optionally mono- or di-substituted with --O--(C.sub.1-6)alkyl,
NH.sub.2, NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; or
R.sup.1 and R.sup.2, together with the carbon to which they are
attached, are linked to form a (C.sub.3-7)cycloalkyl group or a 3-
to 7-membered heterocyclyl, wherein said cycloalkyl and
heterocyclyl are each optionally mono- or di-substituted with
(C.sub.1-6)alkyl; R.sup.3 is H or (C.sub.1-6)alkyl optionally mono-
or di-substituted with --O--(C.sub.1-6)alkyl, NH.sub.2,
NH(C.sub.1-6)alkyl, N((C.sub.1-6)alkyl).sub.2,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2N H.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl or
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2; R.sup.4 is H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-aryl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl or heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted 1 to 3
times with R.sup.41; or R.sup.3 and R.sup.4, together with the N
atom to which they are attached, are linked to form a heterocyclyl
or heteroaryl, wherein said heterocyclyl and heteroaryl are each
optionally substituted 1 to 3 times with R.sup.41; R.sup.41 is each
independently selected from the group consisting of halo, oxo,
cyano, nitro, R.sup.42, --C(.dbd.O)--R.sup.42,
--C(.dbd.O)OR.sup.42, --OR.sup.42, --SR.sup.42, --SOR.sup.42,
--SO.sub.2R.sup.42, --N(R.sup.43)R.sup.42,
--C(.dbd.O)--N(R.sup.43)R.sup.42, --N(R.sup.43)--C(.dbd.O)R.sup.42,
--O--C(.dbd.O)--N(R.sup.43)R.sup.42 and
--SO.sub.2--N(R.sup.43)R.sup.42; R.sup.42 is each independently
selected from the group consisting of H, (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-aryl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl and heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted with 1
to 3 substituents each independently selected from the group
consisting of: halo, cyano, OH, --COON, --O--(C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2N H.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl; R.sup.43
is H or (C.sub.1-6)alkyl.
9. The compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 and R.sup.2 are each
CH.sub.3; or R.sup.1 and R.sup.2 and the carbon to which they are
attached are linked to form a (C.sub.3-4)cycloalkyl group
optionally mono-substituted with (C.sub.1-3)alkyl.
10. The compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is H.
11. The compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is a nitrogen containing
heterocyclyl, optionally mono- or di-substituted with R.sup.41,
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; R.sup.42
is each independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl.
12. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, as a medicament.
13. A method for the treatment or prevention of hepatitis C viral
infection in a human being, comprising administering to said human
being a therapeutically effective amount of a compound according to
claim 1, or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
15. The pharmaceutical composition according to claim 14 further
comprising a therapeutically effective amount of at least one other
antiviral agent.
Description
RELATED APPLICATION
[0001] This application claims benefit of U.S. Ser. No. 61/526,942
filed Aug. 24, 2011, which is herein incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to tetrahydro-azafluorene analogs and
their use in inhibiting entry of hepatitis C virus (HCV) into a
cell, pharmaceutical compositions containing the same, and methods
of using the same as agents for treatment of HCV infection.
BACKGROUND OF THE INVENTION
[0003] It is estimated that at least 170 million persons worldwide
are infected with the hepatitis C virus. Acute HCV infection
progresses to chronic infection in a high number of cases, and, in
some infected individuals, chronic infection leads to serious liver
diseases such as cirrhosis and hepatocellular carcinoma.
[0004] WO 2009/103022 discloses derivatives of substituted fused
ring cycloindoles which inhibit entry of a hepatitis C virus into a
cell. US 2010-0190773 discloses heterocyclic compounds for use as
inhibitors of mitogen-activated protein kinase-activated protein
kinase-2.
SUMMARY OF THE INVENTION
[0005] This invention provides novel compounds which inhibit entry
of hepatitis C virus into a cell as measured by a HCV
pseudo-particle/luciferase assay.
[0006] Further objects of this invention arise for the one skilled
in the art from the following description and the examples.
[0007] Representative embodiments of the compound aspect of the
invention are described below, while other embodiments of the
compound aspect of the invention are described throughout the
specification, for example under the heading "Preferred
Embodiments" beginning at page 20.
[0008] Embodiment 1 provides a compound of Formula (I) or salt
thereof:
##STR00002##
wherein: [0009] X.sup.1 and X.sup.2 are each independently CR.sup.B
or N; [0010] R.sup.B is H, (C.sub.1-6)haloalkyl, halo,
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; [0011] Y.sup.1 and Y.sup.2 are linked to
form a heteroaryl or heterocyclyl ring wherein each said
heterocyclyl and heteroaryl is optionally substituted 1 to 2 times
with R.sup.B; [0012] - - - is a single or double bond; [0013]
R.sup.1 and R.sup.2 are each independently (C.sub.1-6)alkyl
optionally mono- or di-substituted with --O--(C.sub.1-6)alkyl,
NH.sub.2, NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; or
[0014] R.sup.1 and R.sup.2, together with the carbon to which they
are attached, are linked to form a (C.sub.3-7)cycloalkyl group or a
3- to 7-membered heterocyclyl, wherein said cycloalkyl and
heterocyclyl are each optionally mono- or di-substituted with
(C.sub.1-6)alkyl; [0015] R.sup.A is --C(.dbd.O)N(R.sup.3)(R.sup.4),
--C(.dbd.O)O(R.sup.4), heterocyclyl or heteroaryl, wherein each
said heterocyclyl and heteroaryl is optionally substituted 1 to 3
times with R.sup.41; [0016] R.sup.3 is H or (C.sub.1-6)alkyl
optionally mono- or di-substituted with --O--(C.sub.1-6)alkyl,
NH.sub.2, NH(C.sub.1-6)alkyl, N((C.sub.1-6)alkyl).sub.2,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl or
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2; R.sup.4 is H,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-heterocyclyl,
--(C.sub.1-6)alkyl-heteroaryl, aryl, heterocyclyl or heteroaryl,
wherein each said alkyl, cycloalkyl, aryl, heterocyclyl and
heteroaryl, either alone or in combination with another radical, is
optionally substituted 1 to 3 times with R.sup.41; or [0017]
R.sup.3 and R.sup.4, together with the N atom to which they are
attached, are linked to form a heterocyclyl or heteroaryl, wherein
said heterocyclyl and heteroaryl are each optionally substituted 1
to 3 times with R.sup.41; [0018] R.sup.41 is each independently
selected from the group consisting of halo, oxo, cyano, nitro,
R.sup.42, --C(.dbd.O)--R.sup.42, --C(.dbd.O)OR.sup.42, --OR.sup.42,
--SR.sup.42, --SOR.sup.42, --SO.sub.2R.sup.42,
--N(R.sup.43)R.sup.42, --C(.dbd.O)--N(R.sup.43)R.sup.42,
--N(R.sup.43)--C(.dbd.O)R.sup.42,
--O--C(.dbd.O)--N(R.sup.43)R.sup.42 and
--SO.sub.2--N(R.sup.43)R.sup.42; [0019] R.sup.42 is each
independently selected from the group consisting of H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
aryl, heterocyclyl and heteroaryl, either alone or in combination
with another radical, is optionally substituted with 1 to 3
substituents each independently selected from the group consisting
of: [0020] halo, cyano, OH, --COON, --O--(C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl; [0021]
R.sup.43 is H or (C.sub.1-6)alkyl; and [0022] n is 0, 1 or 2.
[0023] Embodiment 2 provides a compound of embodiment 1, or a
pharmaceutically acceptable salt thereof, wherein X.sup.1 is CH or
N.
[0024] Embodiment 3 provides a compound of embodiment 1 or 2, or a
pharmaceutically acceptable salt thereof, wherein X.sup.2 is CH or
N.
[0025] Embodiment 4 provides a compound of embodiments 1, 2 or 3,
or a pharmaceutically acceptable salt thereof, wherein X.sup.1 is
CH.
[0026] Embodiment 5 provides a compound of any one of embodiments
1-4 or a pharmaceutically acceptable salt thereof, wherein X.sup.2
is CH.
[0027] Embodiment 6 provides a compound of any one of embodiments
1-5 or a pharmaceutically acceptable salt thereof, wherein Y.sup.1
and Y.sup.2 are linked to form a 5- or 6-membered heteroaryl ring
optionally substituted 1 to 2 times with (C.sub.1-6)alkyl,
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; and - - - is a single or double
bond.
[0028] Embodiment 7 provides a compound of any one of embodiments
1-6, or a pharmaceutically acceptable salt thereof, wherein Y.sup.1
and Y.sup.2 are linked to form a 5- or 6-membered heteroaryl ring
selected from the group consisting of:
##STR00003##
optionally mono-substituted with (C.sub.1-3)alkyl, NH.sub.2,
NH(C.sub.1-3)alkyl or N((C.sub.1-3)alkyl).sub.2; and is a single or
double bond.
[0029] Embodiment 8 provides a compound of any one of embodiments
1-7, or a pharmaceutically acceptable salt thereof, wherein R.sup.1
is (C.sub.1-3)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2;
R.sup.2 is (C.sub.1-3)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; or R.sup.1 and R.sup.2, together with
the carbon to which they are attached, are linked to form a
(C.sub.3-7)cycloalkyl group, optionally mono- or di-substituted
with (C.sub.1-3)alkyl.
[0030] Embodiment 9 provides a compound of any one of embodiments
1-8, or a pharmaceutically acceptable salt thereof, wherein R.sup.1
and R.sup.2 are each CH.sub.3; or R.sup.1 and R.sup.2 and the
carbon to which they are attached are linked to form a
(C.sub.3-4)cycloalkyl group optionally mono-substituted with
(C.sub.1-3)alkyl.
[0031] Embodiment 10 provides a compound of any one of embodiments
1-9, or a pharmaceutically acceptable salt thereof, wherein R.sup.A
is --C(.dbd.O)N(R.sup.3)(R.sup.4), --C(.dbd.O)O(R.sup.4),
heterocyclyl or heteroaryl, wherein each said heterocyclyl and
heteroaryl is optionally substituted 1 to 2 times with
R.sup.41;
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42, --SO.sub.2R.sup.42 and
--N(R.sup.43)R.sup.42; R.sup.42 is each independently selected from
the group consisting of --(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
aryl, heterocyclyl and heteroaryl, either alone or in combination
with another radical, is optionally substituted with 1 to 2
substituents each independently selected from the group consisting
of: halo, OH, --O--(C.sub.1-6)alkyl, (C.sub.1-6)haloalkyl,
--SO.sub.2NH.sub.2, --SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2 and
(C.sub.1-6)alkyl optionally mono- or di-substituted with OH or
--O--(C.sub.1-6)alkyl; R.sup.43 is H or (C.sub.1-6)alkyl.
[0032] Embodiment 11 provides a compound of any one of embodiments
1-10, or a pharmaceutically acceptable salt thereof, wherein
R.sup.A is --C(.dbd.O)N(R.sup.3)(R.sup.4).
[0033] Embodiment 12 provides a compound of any one of embodiments
1-11, or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is H or (C.sub.1-6)alkyl.
[0034] Embodiment 13 provides a compound of any one of embodiments
1-12, or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is H.
[0035] Embodiment 14 provides a compound of any one of embodiments
1-13 or a pharmaceutically acceptable salt thereof, wherein R.sup.4
is (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
heterocyclyl or heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
R.sup.41;
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42, --C(.dbd.O)OR.sup.42,
--OR.sup.42, --SO.sub.2R.sup.42, --N(H)R.sup.42,
--N(H)--C(.dbd.O)R.sup.42 and --C(.dbd.O)--N(H)R.sup.42; R.sup.42
is each independently selected from the group consisting of H,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-heterocyclyl,
--(C.sub.1-6)alkyl-heteroaryl, heterocyclyl and heteroaryl, wherein
each said alkyl, cycloalkyl, heterocyclyl and heteroaryl, either
alone or in combination with another radical, is optionally mono-
or di-substituted with substitutents each independently selected
from the group consisting of: halo, OH, --O--(C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or
[0036] Embodiment 15 provides a compound of any one of embodiments
1-14, or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is heterocyclyl, optionally mono- or di-substituted with
R.sup.41,
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; R.sup.42
is each independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and
[0037] Embodiment 16 provides a compound of any one of embodiments
1-15, or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is a nitrogen containing heterocyclyl, optionally mono- or
di-substituted with R.sup.41,
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; R.sup.42
is each independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl.
[0038] Embodiment 17 provides a compound of any one of embodiments
1-16, or a pharmaceutically acceptable salt thereof, wherein n is
1.
[0039] Embodiment 18 provides a compound of embodiment 1, or a
pharmaceutically acceptable salt thereof, having a formula
##STR00004##
wherein: [0040] R.sup.1 and R.sup.2 are each independently
(C.sub.1-6)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; or [0041] R.sup.1 and R.sup.2, together
with the carbon to which they are attached, are linked to form a
(C.sub.3-7)cycloalkyl group or a 3- to 7-membered heterocyclyl,
wherein said cycloalkyl and heterocyclyl are each optionally mono-
or di-substituted with (C.sub.1-6)alkyl; [0042] R.sup.3 is H or
(C.sub.1-6)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl,
N((C.sub.1-6)alkyl).sub.2, --C(.dbd.O)--(C.sub.1-6)alkyl,
--SO.sub.2NH.sub.2, --SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl or
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2; [0043] R.sup.4 is H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl or heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted 1 to 3
times with R.sup.41; or [0044] R.sup.3 and R.sup.4, together with
the N atom to which they are attached, are linked to form a
heterocyclyl or heteroaryl, wherein said heterocyclyl and
heteroaryl are each optionally substituted 1 to 3 times with
R.sup.41; [0045] R.sup.41 is each independently selected from the
group consisting of halo, oxo, cyano, nitro, R.sup.42,
--C(.dbd.O)--R.sup.42, --C(.dbd.O)OR.sup.42, --OR.sup.42,
--SR.sup.42, --SOR.sup.42, --SO.sub.2R.sup.42,
--N(R.sup.43)R.sup.42, --C(.dbd.O)--N(R.sup.43)R.sup.42,
--N(R.sup.43)--C(.dbd.O)R.sup.42,
--O--C(.dbd.O)--N(R.sup.43)R.sup.42 and
--SO.sub.2--N(R.sup.43)R.sup.42; [0046] R.sup.42 is each
independently selected from the group consisting of H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
aryl, heterocyclyl and heteroaryl, either alone or in combination
with another radical, is optionally substituted with 1 to 3
substituents each independently selected from the group consisting
of: [0047] halo, cyano, OH, --COON, --O--(C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl; [0048]
R.sup.43 is H or (C.sub.1-6)alkyl.
[0049] Embodiment 19 provides a compound of embodiment 18, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is
(C.sub.1-3)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2;
R.sup.2 is (C.sub.1-3)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; or R.sup.1 and R.sup.2, together with
the carbon to which they are attached, are linked to form a
(C.sub.3-7)cycloalkyl group, optionally mono- or di-substituted
with (C.sub.1-3)alkyl.
[0050] Embodiment 20 provides a compound of embodiment 18 or 19, or
a pharmaceutically acceptable salt thereof, wherein R.sup.1 and
R.sup.2 are each CH.sub.3; or R.sup.1 and R.sup.2 and the carbon to
which they are attached are linked to form a (C.sub.3-4)cycloalkyl
group optionally mono-substituted with (C.sub.1-3)alkyl.
[0051] Embodiment 21 provides a compound of any one of embodiments
18-20, or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is H or (C.sub.1-6)alkyl.
[0052] Embodiment 22 provides a compound of any one of embodiments
18-21, or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is H.
[0053] Embodiment 23 provides a compound of any one of embodiments
18-22, or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
heterocyclyl or heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
R.sup.41;
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42, --C(.dbd.O)OR.sup.42,
--OR.sup.42, --SO.sub.2R.sup.42, --N(H)R.sup.42,
--N(H)--C(.dbd.O)R.sup.42 and --C(.dbd.O)--N(H)R.sup.42; R.sup.42
is each independently selected from the group consisting of H,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-heterocyclyl,
--(C.sub.1-6)alkyl-heteroaryl, heterocyclyl and heteroaryl, wherein
each said alkyl, cycloalkyl, heterocyclyl and heteroaryl, either
alone or in combination with another radical, is optionally mono-
or di-substituted with substitutents each independently selected
from the group consisting of: halo, OH, --O--(C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or
[0054] Embodiment 24 provides a compound of any one of embodiments
18-23, or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is heterocyclyl, optionally mono- or di-substituted with
R.sup.41,
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; R.sup.42
is each independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and
[0055] Embodiment 25 provides a compound of any one of embodiments
18-24, or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is a nitrogen containing heterocyclyl, optionally mono- or
di-substituted with R.sup.41,
R.sup.41 is each independently selected from the group consisting
of R.sup.42, --C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; R.sup.42
is each independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl.
[0056] Another aspect of this invention provides compounds of any
one of the compound embodiments, or a pharmaceutically acceptable
salt thereof, as a medicament.
[0057] Also within the scope of this invention is the use of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, for the manufacture of a medicament for the treatment or
prevention of hepatitis C viral infection in a human being.
[0058] Included within the scope of this invention is a
pharmaceutical composition comprising a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0059] According to a further aspect of this embodiment the
pharmaceutical composition according to this invention further
comprises a therapeutically effective amount of at least one other
antiviral agent.
[0060] The invention also provides the use of a pharmaceutical
composition as described hereinabove for the treatment of a
hepatitis C viral infection in a human being having or at risk of
having the infection.
[0061] Another important aspect of the invention involves a method
of treating or preventing a hepatitis C viral infection in a human
being by administering to the human being an anti-hepatitis C
virally effective amount of a compound of the invention, a
pharmaceutically acceptable salt thereof, or a composition as
described above, alone or in combination with at least one other
antiviral agent, administered together or separately.
[0062] Still another aspect of this invention relates to a method
of inhibiting the entry of hepatitis C virus into a cell comprising
exposing the virus to an effective amount of the compound of the
invention, or a salt thereof, under conditions where entry of
hepatitis C virus into a cell is inhibited.
[0063] Further included in the scope of the invention is the use of
a compound of the invention, or a salt thereof, to inhibit the
entry of hepatitis C virus into a cell.
[0064] Yet another aspect of this invention provides a method of
inhibiting replication of hepatitis C virus through the entry
pathway in a human being by administering a compound of the
invention, including a pharmaceutically acceptable salt
thereof.
[0065] Another aspect of this invention provides a method of
inhibiting the entry of the hepatitis C virus into a cell in a
human being by administering a compound of the invention, including
a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Definitions
[0066] Terms not specifically defined herein should be given the
meanings that would be given to them by one of skill in the art in
light of the disclosure and the context. As used in the
specification, however, unless specified to the contrary, the
following terms have the meaning indicated and the following
conventions are adhered to. In the groups, radicals, or moieties
defined below, the number of carbon atoms is often specified
preceding the group, for example, C.sub.1-6-alkyl means an alkyl
group or radical having 1 to 6 carbon atoms. In general, for groups
comprising two or more subgroups, the first named subgroup is the
radical attachment point, for example, the substituent
"--C.sub.1-3-alkyl-aryl" means an aryl group which is bound to a
C.sub.1-3-alkyl-group, with the C.sub.1-3-alkyl group bound to the
core. Unless specifically stated otherwise, for groups comprising
two or more subgroups, the substituent may be attached to either
subgroup.
[0067] In case a compound of the present invention is depicted in
form of a chemical name and as a formula in case of any discrepancy
the formula shall prevail. An asterisk or the designation, - - - ,
may be used in sub-formulas to indicate the bond which is connected
to the core molecule as defined.
[0068] Unless specifically indicated, throughout the specification
and the appended claims, a given chemical formula or name shall
encompass tautomers and all stereo, optical and geometrical isomers
(e.g. enantiomers, diastereomers, E/Z isomers, atropisomers) and
racemates thereof as well as mixtures in different proportions of
the separate enantiomers, mixtures of diastereomers, or mixtures of
any of the foregoing forms where such isomers and enantiomers
exist, as well as salts, including pharmaceutically acceptable
salts thereof and solvates thereof such as for instance hydrates
including solvates of the free compounds or solvates of a salt of
the compound.
[0069] One skilled in the art would know how to separate, enrich,
or selectively prepare the enantiomers of the compounds of the
present invention. Preparation of pure stereoisomers, e.g.
enantiomers and diastereomers, or mixtures of desired enantiomeric
excess (ee) or enantiomeric purity, are accomplished by one or more
of the many methods of (a) separation or resolution of enantiomers,
or (b) enantioselective synthesis known to those of skill in the
art, or a combination thereof. These resolution methods generally
rely on chiral recognition and include but not limited to
chromatography using chiral stationary phases, enantioselective
host-guest complexation, resolution or synthesis using chiral
auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic
kinetic resolution, or spontaneous enantioselective
crystallization. Such methods are disclosed generally in Chiral
Separation Techniques: A Practical Approach (2nd Ed.), G.
Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R. P. W.
Scott, Chiral Chromatography, John Wiley & Sons, 1999; and
Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem.
Soc., 2000. Furthermore, there are equally well-known methods for
the quantitation of enantiomeric excess or purity, including but
not limited to GC, HPLC, CE, or NMR, and assignment of absolute
configuration and conformation, including but not limited to CD,
ORD, X-ray crystallography, or NMR.
[0070] The term "halo" generally denotes fluorine, chlorine,
bromine and iodine.
[0071] The term "C.sub.1-n-alkyl", wherein n is an integer from 2
to n, either alone or in combination with another radical denotes
an acyclic, saturated, branched or linear hydrocarbon radical with
1 to n C atoms. For example the term C.sub.1-3-alkyl embraces the
radicals H.sub.3C--, H.sub.3C--CH.sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2-- and H.sub.3C--CH(CH.sub.3)--.
[0072] The term "carbocyclyl" or "carbocycle" as used herein,
either alone or in combination with another radical, means a mono-,
bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms.
The term "carbocycle" refers to fully saturated and aromatic ring
systems and partially saturated ring systems. The term "carbocycle"
encompasses fused, bridged and spirocyclic systems.
[0073] The term "C.sub.3-n-cycloalkyl", wherein n is an integer 4
to n, either alone or in combination with another radical, denotes
a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C
atoms. For example the term C.sub.3-7-cycloalkyl includes
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0074] The term "aryl" as used herein, either alone or in
combination with another radical, denotes a carbocyclic aromatic
monocyclic group containing 6 carbon atoms which may be further
fused to at least one other 5- or 6-membered carbocyclic group
which may be aromatic, saturated or unsaturated. Aryl includes, but
is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl,
phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
[0075] The term "heterocyclyl" or "heterocycle" means a saturated
or unsaturated mono- or polycyclic-ring system including aromatic
ring systems containing one or more heteroatoms selected from N, O
or S(O).sub.r, wherein r=0, 1 or 2, consisting of 3 to 14 ring
atoms wherein none of the heteroatoms is part of the aromatic ring.
The term "heterocyclyl" or "heterocycle" is intended to include all
the possible isomeric forms. Thus, the term "heterocyclyl" or
"heterocyclyl" includes the following exemplary structures which
are not depicted as radicals as each form may be attached through a
covalent bond to any atom so long as appropriate valences are
maintained:
##STR00005##
[0076] The term "heteroaryl" means a mono- or polycyclic-ring
system containing one or more heteroatoms selected from N, O or
S(O).sub.r, wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms
wherein at least one of the heteroatoms is part of an aromatic
ring. The term "heteroaryl" is intended to include all the possible
isomeric forms. Thus, the term "heteroaryl" includes the following
exemplary structures which are not depicted as radicals as each
form may be attached through a covalent bond to any atom so long as
appropriate valences are maintained:
##STR00006##
[0077] Many of the terms given above may be used repeatedly in the
definition of a formula or group and in each case have one of the
meanings given above, independently of one another.
[0078] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, and commensurate with a
reasonable benefit/risk ratio.
[0079] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. For example, such salts include acetates,
ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates,
bitartrates, bromides/hydrobromides, Ca-edetates/edetates,
camsylates, carbonates, chlorides/hydrochlorides, citrates,
edisylates, ethane disulfonates, estolates esylates, fumarates,
gluceptates, gluconates, glutamates, glycolates,
glycollylarsnilates, hexylresorcinates, hydrabamines,
hydroxymaleates, hydroxynaphthoates, iodides, isothionates,
lactates, lactobionates, malates, maleates, mandelates,
methanesulfonates, mesylates, methylbromides, methylnitrates,
methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates,
pantothenates, phenylacetates, phosphates/diphosphates,
polygalacturonates, propionates, salicylates, stearates
subacetates, succinates, sulfamides, sulfates, tannates, tartrates,
teoclates, toluenesulfonates, triethiodides, ammonium, benzathines,
chloroprocaines, cholines, diethanolamines, ethylenediamines,
meglumines and procaines. Further pharmaceutically acceptable salts
can be formed with cations from metals like aluminium, calcium,
lithium, magnesium, potassium, sodium, zinc and the like. (also see
Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977),
66, 1-19).
[0080] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a sufficient amount of the
appropriate base or acid in water or in an organic diluent like
ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a
mixture thereof.
[0081] Salts of other acids than those mentioned above which for
example are useful for purifying or isolating the compounds of the
present invention also comprise a part of the invention.
[0082] The term "antiviral agent" as used herein means an agent
(compound or biological) that is effective to inhibit the formation
and/or replication of a virus in a human being. This includes
agents that interfere with either host or viral mechanisms
necessary for the formation and/or replication of a virus in a
human being. Such agents can be selected from: another anti-HCV
agent, HIV inhibitor, HAV inhibitor and HBV inhibitor.
[0083] The term "other anti-HCV agent" as used herein means those
agents that are effective for diminishing or preventing the
progression of hepatitis C related symptoms of disease. Such agents
can be selected from: immunomodulatory agents, inhibitors of HCV
NS3 protease, inhibitors of HCV NS5A, inhibitors of HCV polymerase
or inhibitors of another target in the HCV life cycle. Examples of
anti-HCV agents include, .alpha.-(alpha), .beta.-(beta),
.delta.-(delta), .gamma.-(gamma), .omega.-(omega) or .tau.-(tau)
interferon, pegylated .alpha.-interferon, ribavirin, amantadine,
taribavirin (Viramidine), Nitazoxannide, ABT-267 and
BMS-791325.
[0084] The term "immunomodulatory agent" as used herein includes
those agents (compounds or biologicals) that are effective to
enhance or potentiate the immune system response in a human being.
Immunomodulatory agents include, but are not limited to, inosine
monophosphate dehydrogenase inhibitors, class I interferons, class
II interferons, consensus interferons, asialo-interferons pegylated
interferons and conjugated interferons, including but not limited
to interferons conjugated with other proteins including but not
limited to human albumin. Class I interferons are a group of
interferons that all bind to receptor type I, including both
naturally and synthetically produced class I interferons, while
class II interferons all bind to receptor type II. Examples of
class I interferons include, but are not limited to, .alpha.-,
.beta.-, .delta.-, .omega.-, and .tau.-interferons, while examples
of class II interferons include, but are not limited to,
.gamma.-interferons.
[0085] The term "inhibitor of HCV NS3 protease" as used herein
means an agent (compound or biological) that is effective to
inhibit the function of HCV NS3 protease in a human being.
Inhibitors of HCV NS3 protease include, for example, the candidates
telaprevir, boceprevir, danoprevir, vaniprevir, ABT-450, ACH-1625,
BMS-650032, BI 201335, GS9256, IDX320, MK-5172, VX-985, ACH-2684,
GS9541 and TMC43530.
[0086] The term "inhibitor of HCV polymerase" as used herein means
an agent (compound or biological) that is effective to inhibit the
function of an HCV polymerase in a human being. This includes, for
example, nucleoside analogs or non-nucleosides inhibitors of HCV
polymerase and inhibitors of HCV NS5B polymerase. Inhibitors of HCV
polymerase include for example, the candidates tegobuvir,
filibuvir, BI 207127, RG-7128, IDX184, PSI-7977, MK-3281, VX-222,
ANA598, ABT-333, ABT-072, INX189, PSI-938, RG-7348, JTK-853,
RG-7432, TMC-649128, GS-6620, BMS-791325 and IDX-375.
[0087] The term "inhibitor of HCV NS5A" as used herein means an
agent (compound or biological) that is effective to inhibit the
function of HCV NS5A in a human being. Inhibitors of HCV NS5A
include, for example, ABT-267, BMS-824393, BMS-790052, ITMN-10050,
ITMN-9916, EDP-239, AZD7295, GS-5885, GSK-2336805, IDX-380,
IDX-719, ACH-2928, PPI-437, PPI-668, PPI-833 and PPI-461.
[0088] The term "inhibitor of another target in the HCV life cycle"
as used herein means an agent (compound or biological) that is
effective to inhibit the formation and/or replication of HCV in a
human being by interfering with either host or HCV viral targets
necessary for the HCV life cycle or agents which specifically
inhibit in HCV cell culture assays through an undefined or
incompletely defined mechanism. Inhibitors of another target in the
HCV life cycle include, for example, agents that inhibit viral
targets such as Core, E1, E2, p7, NS2/3 protease, NS3 helicase,
NS4A, NS5A, NS5B polymerase, and internal ribosome entry site
(IRES), or host targets such as cyclophilin A or B,
phosphatidylinositol 4-kinase III.alpha., CD81, SR-B1, Claudin 1,
VAP-A, VAP-B. Specific examples of inhibitors of another target in
the HCV life cycle include SCY-635, ITX5061, NOV-205, AZD7295,
BIT-225, NA808, MK-1220, PF-4878691, MX-3253, GS 9450, TMC-647055,
CF-102, ISIS-14803, GS9190, NIM-811, and DEBIO-025.
[0089] The term "HIV inhibitor" as used herein means an agent
(compound or biological) that is effective to inhibit the formation
and/or replication of HIV in a human being. This includes agents
that interfere with either host or viral mechanisms necessary for
the formation and/or replication of HIV in a human being. HIV
inhibitors include, for example, nucleoside inhibitors,
non-nucleoside inhibitors, protease inhibitors, fusion inhibitors
and integrase inhibitors.
[0090] The term "HAV inhibitor" as used herein means an agent
(compound or biological) that is effective to inhibit the formation
and/or replication of HAV in a human being. This includes agents
that interfere with either host or viral mechanisms necessary for
the formation and/or replication of HAV in a human being. HAV
inhibitors include Hepatitis A vaccines, for example, Havrix.RTM.
(GlaxoSmithKline), VAQTA.RTM. (Merck) and Avaxim.RTM. (Aventis
Pasteur).
[0091] The term "HBV inhibitor" as used herein means an agent
(compound or biological) that is effective to inhibit the formation
and/or replication of HBV in a human being. This includes agents
that interfere with either host or viral mechanisms necessary for
the formation and/or replication of HBV in a human being. HBV
inhibitors include, for example, agents that inhibit HBV viral DNA
polymerase or HBV vaccines. Specific examples of HBV inhibitors
include Lamivudine (Epivir-HBV.RTM.), Adefovir Dipivoxil,
Entecavir, FTC (Coviracil.RTM.), DAPD (DXG), L-FMAU
(Clevudine.RTM.), AM365 (Amrad), Ldt (Telbivudine), monoval-LdC
(Valtorcitabine), ACH-126,443 (L-Fd4C) (Achillion), MCC478 (Eli
Lilly), Racivir (RCV), Fluoro-L and D nucleosides, Robustaflavone,
ICN 2001-3 (ICN), Bam 205 (Novelos), XTL-001 (XTL), Imino-Sugars
(Nonyl-DNJ) (Synergy), HepBzyme; and immunomodulator products such
as: interferon alpha 2b, HE2000 (Hollis-Eden), Theradigm
(Epimmune), EHT899 (Enzo Biochem), Thymosin alpha-1 (Zadaxin.RTM.),
HBV DNA vaccine (PowderJect), HBV DNA vaccine (Jefferon Center),
HBV antigen (OraGen), BayHep B.RTM. (Bayer), Nabi-HB.RTM. (Nabi)
and Anti-hepatitis B (Cangene); and HBV vaccine products such as
the following: Engerix B, Recombivax HB, GenHevac B, Hepacare,
Bio-Hep B, TwinRix, Comvax, Hexavac.
[0092] As used herein, the term "treatment" means the
administration of a compound or composition according to the
present invention to alleviate or eliminate symptoms of the
hepatitis C disease and/or to reduce viral load in a patient.
[0093] As used herein, the term "prevention" means the
administration of a compound or composition according to the
present invention post-exposure of the individual to the virus but
before the appearance of symptoms of the disease, and/or prior to
the detection of the virus in the blood, to prevent the appearance
of symptoms of the disease.
[0094] The term "therapeutically effective amount" means an amount
of a compound according to the invention, which when administered
to a patient in need thereof, is sufficient to effect treatment for
disease-states, conditions, or disorders for which the compounds
have utility. Such an amount would be sufficient to elicit the
biological or medical response of a tissue system, or patient that
is sought by a researcher or clinician. The amount of a compound
according to the invention which constitutes a therapeutically
effective amount will vary depending on such factors as the
compound and its biological activity, the composition used for
administration, the time of administration, the route of
administration, the rate of excretion of the compound, the duration
of the treatment, the type of disease-state or disorder being
treated and its severity, drugs used in combination with or
coincidentally with the compounds of the invention, and the age,
body weight, general health, sex and diet of the patient. Such a
therapeutically effective amount can be determined routinely by one
of ordinary skill in the art having regard to their own knowledge,
the state of the art, and this disclosure.
PREFERRED EMBODIMENTS
[0095] In the following preferred embodiments, groups and
substituents of the compounds of Formula (I) according to this
invention are described in detail.
##STR00007##
[0096] Any and each of the definitions below may be combined with
each other. [0097] X.sup.1: [0098] X.sup.1-A: X.sup.1 is CR.sup.B
or N; [0099] R.sup.B is H, (C.sub.1-6)haloalkyl, halo,
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2. [0100] X.sup.1--B: X.sup.1 is CH or N.
[0101] X.sup.1--C: X.sup.1 is CH. [0102] X.sup.2: [0103] X.sup.2-A:
X.sup.2 is CR.sup.B or N; [0104] R.sup.B is H,
(C.sub.1-6)haloalkyl, halo, --O--(C.sub.1-6)alkyl, NH.sub.2,
NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2. [0105] X.sup.2--B:
X.sup.2 is CH or N. [0106] X.sup.2--C: X.sup.2 is CH. [0107]
Y.sup.1/Y.sup.2: [0108] Y.sup.1/Y.sup.2-A: Y.sup.1 and Y.sup.2 are
linked to form a heteroaryl or heterocyclyl ring wherein each said
heterocyclyl and heteroaryl is optionally substituted 1 to 2 times
with R.sup.B; R.sup.B is H, (C.sub.1-6)haloalkyl, halo,
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; [0109] - - - is a single or double bond.
[0110] Y.sup.1/Y.sup.2--B: Y.sup.1 and Y.sup.2 are linked to form a
5- or 6-membered heteroaryl ring optionally substituted 1 to 2
times with (C.sub.1-6)alkyl, --O--(C.sub.1-6)alkyl, NH.sub.2,
NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; [0111] - - - is a
single or double bond. [0112] Y.sup.1/Y.sup.2--C: Y.sup.1 and
Y.sup.2 are linked to form a 5- or 6-membered heteroaryl ring
selected from the group consisting of:
##STR00008##
[0112] optionally mono-substituted with (C.sub.1-3)alkyl, NH.sub.2,
NH(C.sub.1-3)alkyl or N((C.sub.1-3)alkyl).sub.2; and [0113] - - -
is a single or double bond. [0114] R.sup.1/R.sup.2: [0115]
R.sup.1/R.sup.2-A: R.sup.1 is (C.sub.1-6)alkyl optionally mono- or
di-substituted with --O--(C.sub.1-6)alkyl, NH.sub.2,
NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; [0116] R.sup.2 is
(C.sub.1-6)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; or [0117] R.sup.1 and R.sup.2, together
with the carbon to which they are attached, are linked to form a
(C.sub.3-7)cycloalkyl group or a 3- to 7-membered heterocyclyl,
wherein said cycloalkyl and heterocyclyl are each optionally mono-
or di-substituted with (C.sub.1-6)alkyl. [0118] R.sup.1/R.sup.2--B:
R.sup.1 is (C.sub.1-3)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; [0119] R.sup.2 is (C.sub.1-3)alkyl
optionally mono- or di-substituted with --O--(C.sub.1-6)alkyl,
NH.sub.2, NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; or
[0120] R.sup.1 and R.sup.2, together with the carbon to which they
are attached, are linked to form a (C.sub.3-7)cycloalkyl group,
optionally mono- or di-substituted with (C.sub.1-3)alkyl. [0121]
R.sup.1/R.sup.2--C: R.sup.1 and R.sup.2 are each CH.sub.3; or
[0122] R.sup.1 and R.sup.2 and the carbon to which they are
attached are linked to form a (C.sub.3-4)cycloalkyl group
optionally mono-substituted with (C.sub.1-3)alkyl. [0123] R.sup.A:
[0124] R.sup.A-A: R.sup.A is --C(.dbd.O)N(R.sup.3)(R.sup.4),
--C(.dbd.O)O(R.sup.4), heterocyclyl or heteroaryl, wherein each
said heterocyclyl and heteroaryl is optionally substituted 1 to 3
times with R.sup.41; [0125] R.sup.41 is each independently selected
from the group consisting of halo, oxo, cyano, nitro, R.sup.42,
--C(.dbd.O)--R.sup.42, --C(.dbd.O)OR.sup.42, --OR.sup.42,
--SR.sup.42, --SOR.sup.42, --SO.sub.2R.sup.42,
--N(R.sup.43)R.sup.42, --C(.dbd.O)--N(R.sup.43)R.sup.42,
--N(R.sup.43)--C(.dbd.O)R.sup.42,
--O--C(.dbd.O)--N(R.sup.43)R.sup.42 and
--SO.sub.2--N(R.sup.43)R.sup.42; [0126] R.sup.42 is each
independently selected from the group consisting of H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl and heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted with 1
to 3 substituents each independently selected from the group
consisting of: [0127] halo, cyano, OH, --COON,
--O--(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl; and
[0128] R.sup.43 is H or (C.sub.1-6)alkyl. [0129] R.sup.A--B:
R.sup.A is --C(.dbd.O)N(R.sup.3)(R.sup.4), --C(.dbd.O)O(R.sup.4),
heterocyclyl or heteroaryl, wherein each said heterocyclyl and
heteroaryl is optionally substituted 1 to 2 times with R.sup.41;
[0130] R.sup.41 is each independently selected from the group
consisting of R.sup.42, --C(.dbd.O)--R.sup.42, --SO.sub.2R.sup.42
and --N(R.sup.43)R.sup.42; [0131] R.sup.42 is each independently
selected from the group consisting of --(C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-heterocyclyl,
--(C.sub.1-6)alkyl-heteroaryl, aryl, heterocyclyl and heteroaryl,
wherein each said alkyl, cycloalkyl, aryl, heterocyclyl and
heteroaryl, either alone or in combination with another radical, is
optionally substituted with 1 to 2 substituents each independently
selected from the group consisting of: [0132] halo, OH,
--O--(C.sub.1-6)alkyl, (C.sub.1-6)haloalkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2 and
(C.sub.1-6)alkyl optionally mono- or di-substituted with OH or
--O--(C.sub.1-6)alkyl; [0133] R.sup.43 is H or (C.sub.1-6)alkyl.
[0134] R.sup.A--C: R.sup.A is --C(.dbd.O)N(R.sup.3)(R.sup.4).
[0135] R.sup.3: [0136] R.sup.3-A: R.sup.3 is H or (C.sub.1-6)alkyl
optionally mono- or di-substituted with --O--(C.sub.1-6)alkyl,
NH.sub.2, NH(C.sub.1-6)alkyl, N((C.sub.1-6)alkyl).sub.2,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl or
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2. [0137] R.sup.3--B: R.sup.3
is H or (C.sub.1-6)alkyl. [0138] R.sup.3--C: R.sup.3 is H. [0139]
R.sup.4: [0140] R.sup.4-A: R.sup.4 is H, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl or heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted 1 to 3
times with R.sup.41; or [0141] R.sup.3 and R.sup.4, together with
the N atom to which they are attached, are linked to form a
heterocyclyl or heteroaryl, wherein said heterocyclyl and
heteroaryl are each optionally substituted 1 to 3 times with
R.sup.41; [0142] R.sup.41 is each independently selected from the
group consisting of halo, oxo, cyano, nitro, R.sup.42,
--C(.dbd.O)--R.sup.42, --C(.dbd.O)OR.sup.42, --OR.sup.42,
--SR.sup.42, --SOR.sup.42, --SO.sub.2R.sup.42,
--N(R.sup.43)R.sup.42, --C(.dbd.O)--N(R.sup.43)R.sup.42,
--N(R.sup.43)--C(.dbd.O)R.sup.42,
--O--C(.dbd.O)--N(R.sup.43)R.sup.42 and
--SO.sub.2--N(R.sup.43)R.sup.42; [0143] R.sup.42 is each
independently selected from the group consisting of H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl and heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted with 1
to 3 substituents each independently selected from the group
consisting of: [0144] halo, cyano, OH, --COON,
--O--(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl; [0145]
R.sup.43 is H or (C.sub.1-6)alkyl. [0146] R.sup.4--B: R.sup.4 is
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
heterocyclyl or heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
R.sup.41; [0147] R.sup.41 is each independently selected from the
group consisting of R.sup.42, --C(.dbd.O)--R.sup.42,
--C(.dbd.O)OR.sup.42, --OR.sup.42, --SO.sub.2R.sup.42,
--N(H)R.sup.42, --N(H)--C(.dbd.O)R.sup.42 and
--C(.dbd.O)--N(H)R.sup.42; [0148] R.sup.42 is each independently
selected from the group consisting of H, (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-heterocyclyl,
--(C.sub.1-6)alkyl-heteroaryl, heterocyclyl and heteroaryl, wherein
each said alkyl, cycloalkyl, heterocyclyl and heteroaryl, either
alone or in combination with another radical, is optionally mono-
or di-substituted with substitutents each independently selected
from the group consisting of: [0149] halo, OH,
--O--(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--SO.sub.2NH.sub.2, --SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl. [0150]
R.sup.4--C: R.sup.4 is heterocyclyl, optionally mono- or
di-substituted with R.sup.41, [0151] R.sup.41 is each independently
selected from the group consisting of R.sup.42,
--C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; [0152] R.sup.42 is
each independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: [0153] halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl. [0154]
R.sup.4-D: R.sup.4 is a nitrogen containing heterocyclyl,
optionally mono- or di-substituted with R.sup.41, [0155] R.sup.41
is each independently selected from the group consisting of
R.sup.42, --C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; [0156]
R.sup.42 is each independently selected from the group consisting
of (C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: [0157] halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl. [0158] n:
[0159] n-A: n is 0, 1 or 2. [0160] n-B: n is 1.
[0161] Examples of preferred subgeneric embodiments of the present
invention are set forth in the following table, wherein each
substituent group of each embodiment is defined according to the
definitions set forth above:
TABLE-US-00001 X.sup.1 X.sup.2 R.sup.1/R.sup.2 R.sup.A R.sup.3
R.sup.4 n Y.sup.1/Y.sup.2 E-1 X.sup.1-A X.sup.2-A R.sup.1/R.sup.2-B
R.sup.A-C R.sup.3-B R.sup.4-B n-A Y.sup.1/Y.sup.2-B E-2 X.sup.1-B
X.sup.2-B R.sup.1/R.sup.2-B R.sup.A-C R.sup.3-B R.sup.4-A n-B
Y.sup.1/Y.sup.2-B E-3 X.sup.1-B X.sup.2-B R.sup.1/R.sup.2-C
R.sup.A-B R.sup.3-B R.sup.4-B n-B Y.sup.1/Y.sup.2-A E-4 X.sup.1-C
X.sup.2-C R.sup.1/R.sup.2-C R.sup.A-B R.sup.3-B R.sup.4-B n-B
Y.sup.1/Y.sup.2-B E-5 X.sup.1-C X.sup.2-C R.sup.1/R.sup.2-C
R.sup.A-C R.sup.3-C R.sup.4-C n-B Y.sup.1/Y.sup.2-C E-6 X.sup.1-B
X.sup.2-B R.sup.1/R.sup.2-C R.sup.A-B R.sup.3-B R.sup.4-D n-B
Y.sup.1/Y.sup.2-A E-7 X.sup.1-C X.sup.2-C R.sup.1/R.sup.2-C
R.sup.A-B R.sup.3-B R.sup.4-D n-B Y.sup.1/Y.sup.2-B E-8 X.sup.1-C
X.sup.2-C R.sup.1/R.sup.2-C R.sup.A-C R.sup.3-C R.sup.4-D n-B
Y.sup.1/Y.sup.2-C
[0162] In the following more preferred embodiments, groups and
substituents of the compounds having the formula are described in
detail.
##STR00009##
[0163] Any and each of the definitions below may be combined with
each other. [0164] R.sup.1/R.sup.2: [0165] R.sup.1/R.sup.2-A:
R.sup.1 and R.sup.2 are each independently (C.sub.1-6)alkyl
optionally mono- or di-substituted with --O--(C.sub.1-6)alkyl,
NH.sub.2, NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; or
R.sup.1 and R.sup.2, together with the carbon to which they are
attached, are linked to form a (C.sub.3-7)cycloalkyl group or a 3-
to 7-membered heterocyclyl, wherein said cycloalkyl and
heterocyclyl are each optionally mono- or di-substituted with
(C.sub.1-6)alkyl. [0166] R.sup.1/R.sup.2--B: R.sup.1 is
(C.sub.1-3)alkyl optionally mono- or di-substituted with
--O--(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6)alkyl or
N((C.sub.1-6)alkyl).sub.2; [0167] R.sup.2 is (C.sub.1-3)alkyl
optionally mono- or di-substituted with --O--(C.sub.1-6)alkyl,
NH.sub.2, NH(C.sub.1-6)alkyl or N((C.sub.1-6)alkyl).sub.2; or
[0168] R.sup.1 and R.sup.2, together with the carbon to which they
are attached, are linked to form a (C.sub.3-7)cycloalkyl group,
optionally mono- or di-substituted with (C.sub.1-3)alkyl. [0169]
R.sup.1/R.sup.2--C: R.sup.1 and R.sup.2 are each CH.sub.3; or
[0170] R.sup.1 and R.sup.2 and the carbon to which they are
attached are linked to form a (C.sub.3-4)cycloalkyl group
optionally mono-substituted with (C.sub.1-3)alkyl. [0171] R.sup.3:
[0172] R.sup.3-A: R.sup.3 is H or (C.sub.1-6)alkyl optionally mono-
or di-substituted with --O--(C.sub.1-6)alkyl, NH.sub.2,
NH(C.sub.1-6)alkyl, N((C.sub.1-6)alkyl).sub.2,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl or
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2. [0173] R.sup.3--B: R.sup.3
is H or (C.sub.1-6)alkyl. [0174] R.sup.3--C: R.sup.3 is H. [0175]
R.sup.4: [0176] R.sup.4-A: R.sup.4 is H, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl or heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted 1 to 3
times with R.sup.41; or [0177] R.sup.3 and R.sup.4, together with
the N atom to which they are attached, are linked to form a
heterocyclyl or heteroaryl, wherein said heterocyclyl and
heteroaryl are each optionally substituted 1 to 3 times with
R.sup.41; [0178] R.sup.41 is each independently selected from the
group consisting of halo, oxo, cyano, nitro, R.sup.42,
--C(.dbd.O)--R.sup.42, --C(.dbd.O)OR.sup.42, --OR.sup.42,
--SR.sup.42, --SOR.sup.42, --SO.sub.2R.sup.42,
--N(R.sup.43)R.sup.42, --C(.dbd.O)--N(R.sup.43)R.sup.42,
--N(R.sup.43)--C(.dbd.O)R.sup.42,
--O--C(.dbd.O)--N(R.sup.43)R.sup.42 and
--SO.sub.2--N(R.sup.43)R.sup.42; [0179] R.sup.42 is each
independently selected from the group consisting of H,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
aryl, heterocyclyl and heteroaryl, wherein each said alkyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in
combination with another radical, is optionally substituted with 1
to 3 substituents each independently selected from the group
consisting of: [0180] halo, cyano, OH, --COON,
--O--(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--C(.dbd.O)--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl; [0181]
R.sup.43 is H or (C.sub.1-6)alkyl. [0182] R.sup.4--B: R.sup.4 is
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
--(C.sub.1-6)alkyl-heterocyclyl, --(C.sub.1-6)alkyl-heteroaryl,
heterocyclyl or heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
R.sup.41; [0183] R.sup.41 is each independently selected from the
group consisting of R.sup.42, --C(.dbd.O)--R.sup.42,
--C(.dbd.O)OR.sup.42, --OR.sup.42, --SO.sub.2R.sup.42,
--N(H)R.sup.42, --N(H)--C(.dbd.O)R.sup.42 and
--C(.dbd.O)--N(H)R.sup.42; [0184] R.sup.42 is each independently
selected from the group consisting of H, (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, --(C.sub.1-6)alkyl-heterocyclyl,
--(C.sub.1-6)alkyl-heteroaryl, heterocyclyl and heteroaryl, wherein
each said alkyl, cycloalkyl, heterocyclyl and heteroaryl, either
alone or in combination with another radical, is optionally mono-
or di-substituted with substitutents each independently selected
from the group consisting of: [0185] halo, OH,
--O--(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, (C.sub.1-6)haloalkyl,
--SO.sub.2NH.sub.2, --SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-6)alkyl,
--C(.dbd.O)--N((C.sub.1-6)alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl optionally
mono- or di-substituted with OH or --O--(C.sub.1-6)alkyl. [0186]
R.sup.4--C: R.sup.4 is heterocyclyl, optionally mono- or
di-substituted with R.sup.41, [0187] R.sup.41 is each independently
selected from the group consisting of R.sup.42,
--C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; [0188] R.sup.42 is
each independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: [0189] halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl. [0190]
R.sup.4-D: R.sup.4 is a nitrogen containing heterocyclyl,
optionally mono- or di-substituted with R.sup.41, [0191] R.sup.41
is each independently selected from the group consisting of
R.sup.42, --C(.dbd.O)--R.sup.42 and --SO.sub.2R.sup.42; [0192]
R.sup.42 is each independently selected from the group consisting
of (C.sub.1-6)alkyl, (C.sub.5-7)cycloalkyl,
--(C.sub.1-4)alkyl-heterocyclyl, --(C.sub.1-4)alkyl-heteroaryl,
heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl,
heterocyclyl and heteroaryl, either alone or in combination with
another radical, is optionally mono- or di-substituted with
substitutents each independently selected from the group consisting
of: [0193] halo, OH, --O--(C.sub.1-6)alkyl, --SO.sub.2NH.sub.2,
--SO.sub.2--NH(C.sub.1-6)alkyl,
--SO.sub.2--N((C.sub.1-6)alkyl).sub.2, --SO.sub.2(C.sub.1-6)alkyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N((C.sub.1-6)alkyl).sub.2,
--NH--C(.dbd.O)(C.sub.1-6)alkyl and (C.sub.1-6)alkyl.
[0194] Examples of more preferred subgeneric embodiments of the
present invention are set forth in the following table, wherein
each substituent group of each embodiment is defined according to
the definitions set forth above:
TABLE-US-00002 R.sup.1/R.sup.2 R.sup.3 R.sup.4 E-9
R.sup.1/R.sup.2-A R.sup.3-B R.sup.4-C E-10 R.sup.1/R.sup.2-B
R.sup.3-B R.sup.4-B E-11 R.sup.1/R.sup.2-B R.sup.3-B R.sup.4-C E-12
R.sup.1/R.sup.2-B R.sup.3-B R.sup.4-D E-13 R.sup.1/R.sup.2-C
R.sup.3-C R.sup.4-B E-14 R.sup.1/R.sup.2-C R.sup.3-C R.sup.4-C E-15
R.sup.1/R.sup.2-C R.sup.3-C R.sup.4-D
[0195] Examples of most preferred compounds according to this
invention are each single compound listed in Tables 1-5.
Pharmaceutical Composition
[0196] Suitable preparations for administering the compounds of the
invention will be apparent to those with ordinary skill in the art
and include for example tablets, pills, capsules, suppositories,
lozenges, troches, solutions, syrups, elixirs, sachets,
injectables, inhalatives and powders. The content of the
pharmaceutically active compound(s) should be in the range from
0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as
a whole.
[0197] Suitable tablets may be obtained, for example, by mixing one
or more compounds according to the invention with known excipients,
for example inert diluents, carriers, disintegrants, adjuvants,
surfactants, binders and/or lubricants. The tablets may also
consist of several layers.
Combination Therapy
[0198] Combination therapy is contemplated wherein a compound of
the invention, or a pharmaceutically acceptable salt thereof, is
co-administered with at least one additional agent selected from:
an antiviral agent, an immunomodulatory agent, an inhibitor of HCV
NS3 protease, an inhibitor of HCV polymerase, an inhibitor of HCV
NS5A, an inhibitor of another target in the HCV life cycle, an HIV
inhibitor, an HAV inhibitor and an HBV inhibitor. These additional
agents may be combined with the compounds of this invention to
create a single pharmaceutical dosage form. Alternatively these
additional agents may be separately administered to the patient as
part of a multiple dosage form, for example, using a kit. Such
additional agents may be administered to the patient prior to,
concurrently with, or following the administration of a compound of
the invention, or a pharmaceutically acceptable salt thereof.
[0199] The dose range of the compounds of the invention applicable
per day is usually from 0.01 to 100 mg/kg of body weight,
preferably from 0.1 to 50 mg/kg of body weight. Each dosage unit
may conveniently contain from 5% to 95% active compound (w/w).
Preferably such preparations contain from 20% to 80% active
compound.
[0200] The actual pharmaceutically effective amount or therapeutic
dosage will of course depend on factors known by those skilled in
the art such as age and weight of the patient, route of
administration and severity of disease. In any case the combination
will be administered at dosages and in a manner which allows a
pharmaceutically effective amount to be delivered based upon
patient's unique condition.
[0201] When the composition of this invention comprises a
combination of a compound of the invention and one or more
additional therapeutic or prophylactic agent, both the compound and
the additional agent should be present at dosage levels of between
about 10 to 100%, and more preferably between about 10 and 80% of
the dosage normally administered in a monotherapy regimen.
EXAMPLES
[0202] Other features and advantages of the present invention will
become apparent from the following more detailed Examples which
illustrate, by way of example, the principles of the invention.
Temperatures are given in degrees Celsius. Solution percentages
express a weight to volume relationship, and solution ratios
express a volume to volume relationship, unless stated
otherwise.
[0203] Compounds and intermediates can be purified on a Teledyne
ISCO Combiflash R.sub.f System at 254 nm using commercial normal
phase silica 4-120 g Redisep R.sub.f or Silicycle columns at a flow
rate of 18-85 mL/min depending on column size. Mass spectral
analyses are recorded using flow injection analysis mass
spectrometry or Waters Acquity Ultraperformance LC System
consisting of a sample organizer, PDA detector, column manager,
sample manager, binary solvent manager and SQ detector.
[0204] Preparative RP-HPLC is performed under standard conditions
using one of the following specific measuring conditions:
[0205] Compounds are purified by preparative RP-HPLC under standard
conditions using a Waters SunFire Prep OBD C18 column (5 .mu.m,
19.times.50 mm) eluting with a linear MeOH gradient containing 10
mM Ammonium Formate (pH 3.8) over 10 min at 30 ml/min. Fractions
containing the desired product are pooled and lyophilized
[0206] Compounds are purified by preparative RP-HPLC under standard
conditions using a Waters XBridge Prep OBD C18 (5 .mu.m,
19.times.50 mm) eluting with a linear MeOH gradient containing 10
mM Ammonium Bicarbonate (pH 10) over 10 min at 30 ml/min. Fractions
containing the desired product are pooled and lyophilized.
[0207] Analytical UPLC is performed under standard conditions using
one of the following specific measuring conditions:
[0208] Analytical UPLC is also carried out under standard
conditions using (AB) a Waters ACQUITY UPLC BEH C18 column (1.8
.mu.m, 2.1.times.30 mm) eluting with a linear methanol gradient
containing 10 mM Ammonium Bicarbonate (pH 10) over 2.2 min at 0.75
ml/min or (AF) a Waters ACQUITY UPLC.RTM. HSS C18 column (1.8
.mu.m, 2.1.times.30 mm) eluting with a linear MeOH gradient
containing 10 mM Ammonium Formate (pH 3.8) over 2.3 min at 0.8
ml/min.
[0209] Analytical UPLC is also carried out under standard
conditions using a Waters ACQUITY UPLC HSS C18 column (1.8 .mu.m,
2.1.times.30 mm) eluting with a linear MeOH gradient containing 10
mM Ammonium Formate (pH 3.8) over 2.3 min at 0.8 ml/min.
[0210] Abbreviations used in the examples include:
Ac: acetyl; AcOH: acetic acid; BOC or Boc: tert-butyloxycarbonyl;
Bu: butyl; DCM: dichloromethane; DIPEA: diisopropylethylamine;
DMAc: dimethylacetamide; DMAP: 4-dimethylaminopyridine; DMEM:
Dulbecco's modified Eagle's medium; DMF: N,N-dimethylformamide;
DMSO: dimethylsulfoxide; dppf: 1,1'-diphenylphosphinylferrocene;
EDCI: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride; Et: ethyl; Et.sub.2O: diethyl ether; EtOAc: ethyl
acetate; EtOH: ethanol; FBS: Fetal bovine serum; HATU:
[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate]; HEPES:
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; Hex: hexanes;
HPLC: high performance liquid chromatography; HSS: high strength
silica; i-Pr: isopropyl; LiHMDS: lithium bis(trimethylsilyl)amide;
Me: methyl; MeCN: acetonitrile; MeOH: methanol; MS: mass
spectrometry (FIA MS-flow injection analysis mass spectrometry
UPLC: Ultraperformance Liquid Chromatography); m/z: mass-to-charge
ratio; [M+H].sup.+: protonated molecular ion; NEAA: non-essential
amino acids; NMP: N-methyl pyrrolidinone; OBD: optimum bed density;
PDA: photodiode array; RP: reverse phase; RT: room temperature (18
to 22.degree. C.); TEA: triethylamine; TFA: trifluoroacetic acid;
THF: tetrahydrofuran; TMS: trimethylsilyl; VSV: vesicular
stomatitis virus.
Example 1
Preparation of Intermediates 1a3 and 1a5
##STR00010##
[0211] Step 1:
[0212] To a 0.degree. C. mixture of NaH (60% in oil, 0.65 g, 15.0
mmol) in EtOH (0.1 mL) and ether (30 mL) is added a solution of
cyclohexanone (1.9 g, 15.0 mmol, Combi-blocks) and ethylformate
(1.8 mL, 22.5 mmol) in ether (40 mL) over a period of 1 h. The
reaction mixture is allowed to warm to RT overnight. EtOH (1.5 mL)
is added and the reaction mixture is stirred for 1 h. Water (40 mL)
is added and the ether layer is washed with water. The aqueous
layer is acidified with 6N HCl and extracted with ether. The
combined organic extracts are washed with water, brine, dried over
MgSO.sub.4 and concentrated to afford 1a1 which is used as such in
the next step.
Step 2:
[0213] 1a1 (1.15 g, 7.5 mmol) is dissolved in MeOH (30 mL), NaOAc
(1.4 g, 16 mmol) and water (30 mL) are added and the resulting
solution 1-1 is cooled to 0.degree. C. In a separate vessel,
4-aminobenzoic acid (1.0 g, 7.5 mmol, Aldrich) is cooled to
0.degree. C., taken up in water (30 mL) and concentrated HCl is
added (2.2 mL). To this is added a saturated solution of NaNO.sub.2
(0.9 g, 15 mmol, 9 mL of water). The solution is then added to
solution 1-1 and the reaction mixture is allowed to stir for 30
min. The precipitate is filtered, washed with water and dried to
provide 1a2.
Step 3:
[0214] 1a2 (1.75 g, 6.4 mmol) is taken up in formic acid (70 mL)
and heated at 100.degree. C. for 12 h. The reaction is cooled to RT
and poured into cold water (100 mL). The resulting precipitate is
filtered, washed with cold water and dried to provide 1a3.
Step 4:
[0215] 1a3 suspended in MeOH (25 mL) is treated with diazomethane
(0.68M, 10 mL). MeOH (50 mL) and diazomethane (15 mL) are again
added and the reaction mixture is stirred at RT for 1 h. The
solvents are evaporated in vacuo and the residue is dried under
vacuum to provide 1a4.
Step 5:
[0216] To 1a4 (2.10 g, 7.74 mmol) in DMF (20 mL), is added NaH (60%
in oil, 350 mg, 8.75 mmol). After 5 min, 4-methoxybenzyl chloride
(1.16 mL, 8.55 mmol) is added and the resulting solution is stirred
at RT overnight. The reaction mixture is diluted with EtOAc, then
washed with an aqueous solution of saturated NaHCO.sub.3, H.sub.2O
(2.times.) and brine, dried over MgSO.sub.4, concentrated and
purified by Combiflash (90:10 Hex/EtOAc) to afford 1a5.
Example 2
Preparation of Intermediate 2a4
##STR00011## ##STR00012##
[0217] Step 1:
[0218] To 1a5 (1.00 g, 2.56 mmol) and ethyl formate (500 .mu.L,
6.22 mmol) in THF (15 mL) is added NaH (60% in oil, 306.5 mg, 7.66
mmol) at 0.degree. C. This mixture is stirred for 10 min, warmed to
RT, and then stirred for 2 h. EtOAc and 1M HCl are added. The
layers are separated and the organic layer is washed with water and
brine, dried with Na.sub.2SO.sub.4 and concentrated to provide
2a1.
Step 2:
[0219] To a solution of 2a1 (250 mg, 0.58 mmol) in DMF (2.0 mL) and
EtOH (3.0 mL) is added 2M hydrazine in THF (2.0 mL). The mixture is
heated to 90.degree. C. and stirred for 1 h. EtOAc and 1M HCl are
added. The layers are separated and the organic layer is washed
with water and brine, dried with Na.sub.2SO.sub.4 and concentrated
to provide crude 2a2 that is used as such.
Step 3:
[0220] The crude 2a2 obtained in step 2 is dissolved in DMF (3.0
mL) and 1M NaOH (2.0 mL, 2.00 mmol) is added. The mixture is
stirred for 16 h. EtOAc and 1M HCl are added. The layers are
separated and the organic layer is washed with water and brine,
dried with Na.sub.2SO.sub.4 and concentrated to provide crude 2a3
that is used as such.
Step 4:
[0221] The crude 2a3 obtained in step 3 is dissolved in TFA (2.0
mL) and triflic anhydride (30 .mu.l) is added. The mixture is
stirred for 2 h, concentrated to dryness and purified by Combiflash
(0:100 to 5:95, MeOH/DCM) to provide 2a4.
Example 3
Preparation of Intermediate 3a12
##STR00013## ##STR00014##
[0222] Step 1:
[0223] Lithium aluminum hydride bis(THF) (432 mL, 1.0 M in toluene,
432 mmol) is added over a period of 1.25 h to a -20.degree. C.
(internal temperature) solution of diethyl
cyclobutane-1,1-dicarboxylate (57.5 g, 288 mmol, VWR) in THF (1.00
L). The reaction mixture is allowed to warm to an internal
temperature of 0.degree. C. over 1 h, and kept at 0.degree. C. for
0.5 h. While maintaining an internal temperature of 0.degree. C.,
the reaction mixture is quenched sequentially with water (60 mL),
15 wt. % aqueous NaOH (60 mL) and water (170 mL). The reaction
mixture is further diluted with THF (500 mL), and then stirred as
it warms to RT. The reaction mixture is filtered through Celite and
the Celite pad is rinsed with THF. The filtrate is dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure
to provide 3a1.
Step 2:
[0224] Oxalyl chloride (61.5 mL, 708 mmol) is added over 1.5 h to a
-80.degree. C. (internal temperature; Et.sub.2O/dry-ice bath is
used for cooling) solution of DMSO (50.2 mL, 708 mmol) in DCM (3.00
L). The reaction mixture is allowed to stir at -80.degree. C. for
0.5 h, and then a solution of 3a1 (30.9 g, 266 mmol) in DCM (500
mL) is added over 1 h while maintaining an internal temperature of
-80.degree. C. The reaction mixture is stirred for 0.5 h at
-80.degree. C., and then TEA (297 mL, 2.13 mol) is added over 1 h
while keeping an internal temperature of -80.degree. C. The cooling
bath is removed, and the reaction mixture is allowed to warm to
10.degree. C. over 4 h. The crude material containing 3a2 is used
as such in the next step.
Step 3:
[0225] The solution containing 3a2 is transferred to an addition
funnel connected to a 12 L multi-neck flack fitted with a
mechanical stirrer. The reaction mixture is added over 40 min to a
solution of triethyl phosphonoacetate (141 mL, 708 mmol), anhydrous
LiCl (60.0 g, 1.42 mol) and DIPEA (492 mL, 2.83 mol) in MeCN (2.12
L). The resulting mixture is stirred at RT for 16 h, and then
concentrated under reduced pressure to -500 mL. The suspension is
diluted with Et.sub.2O (4.0 L) and water (2.0 L). The layers are
separated and the aqueous phase is extracted with Et.sub.2O (4.0
L). The combined organic extracts are washed with water (2.0 L),
aqueous saturated NaHCO.sub.3 (2.0 L) and aqueous saturated NaCl
(2.0 L), dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated under reduced pressure and purified by Combiflash (5%
EtOAc/Hex) to provide 3a3.
Step 4:
[0226] Palladium on activated carbon (22.5 g, 10 wt. %, wet,
Degussa type E101 NE/W, 10.6 mmol, Strem) is added to a solution of
3a3 (53.3 g, 212 mmol) in EtOAc (2.10 L). The suspension is divided
approximately equally between two 2 L round-bottom flasks, and each
flask is capped with an airfree adapter fitted with a large balloon
filled with hydrogen gas. The systems are purged with hydrogen gas
(3.times.), and then allowed to stir under a hydrogen atmosphere
for 2 days. The reaction mixtures are filtered through Celite with
EtOAc washings (3.times.100 mL). The filtrate is concentrated under
reduced and purified by Combiflash (5% EtOAc/Hex) to provide
3a4.
Step 5:
[0227] Potassium tert-butoxide (39.0 g, 347 mmol) is added to a
solution of 3a4 (44.5 g, 174 mmol) in THF (1.75 L). The resulting
mixture is heated to reflux, and then stirred at reflux for 1 h.
The reaction mixture is cooled to an internal temperature of
-10.degree. C., quenched with aqueous 1M HCl (700 mL), and then
allowed to warm to RT. The solution is diluted with Et.sub.2O (4.0
L) and the layers are separated. The organic layer is washed with
aqueous saturated NaCl (700 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and
purified by Combiflash (2.5% EtOAc/Hex) to provide 3a5.
Step 6:
[0228] 3a5 (750 mg, 3.58 mmol) is charged in a round bottom flask
with water (10 mL) and 5N NaOH (0.78 mL, 3.92 mmol) and the
resulting mixture is stirred for 24 h. The reaction mixture is
transferred to a separatory funnel and washed with ether
(2.times.). The aqueous layer is transferred back to its original
flask, cooled to 0.degree. C. and quenched with 1 equivalent of 6N
HCl (until pH is approximately 4-5). The mixture is stirred at
0.degree. C. for 25 min to afford 3a6 which is used as such in the
next step.
Step 7:
[0229] To the aqueous solution of 3a6 (619 mg, 3.40 mmol) at
0.degree. C. is added over 20 min a solution of
4-bromobenzenediazonium tetrafluoroborate (920 mg, 3.40 mmol) in
water (12 mL). The resulting mixture is stirred at 0.degree. C. for
10 min, and then allowed to stir at RT for 30 min. The reaction
mixture is filtered and the residue is dissolved in EtOAc, washed
with brine, dried over MgSO.sub.4, filtered and concentrated under
reduced pressure to provide 3a7, which is used as such in the next
step.
Step 8:
[0230] 3a7 (1.09 g, 3.40 mmol) is suspended in MeCN (27 mL) and an
aqueous solution of sulfuric acid (1.8M, 5.7 mL, 10.2 mmol) is
added. The reaction mixture is stirred for 4 h at 80.degree. C.,
then cooled to RT and concentrated under reduced pressure to remove
approximately half of the MeCN. Water (50 mL) is added, and the
mixture is stirred for 1 h. The mixture is filtered and the residue
is purified by Combiflash (100% Chloroform, then Chloroform/MeOH
95%/5%) to give 3a8.
Step 9:
[0231] To 3a8 (1.00 g, 3.29 mmol) and ethyl formate (0.645 mL, 8.02
mmol) in THF (25.00 mL) is added NaH (60% in oil, 420.8 mg, 10.52
mmol) at 0.degree. C. This mixture is stirred for 10 min at
0.degree. C., warmed to RT and stirred for 2 h. EtOAc and 1N HCl
are added. The layers are separated and the organic layer is washed
with water and brine, dried over MgSO.sub.4, filtered and
concentrated to give 3a9.
Step 10:
[0232] 3a9 (1.09 g, 3.28 mmol) is dissolved in EtOH (15.00 mL) and
hydrazine hydrate (3.00 mL, 96.47 mmol) is added. The reaction
mixture is stirred at 90.degree. C. for 2 h. EtOAc and 1N HCl
(aqueous) are added. The layers are separated and the organic layer
is washed with water and brine, dried over MgSO.sub.4, filtered and
concentrated under vacuum. The crude material is purified by
Combiflash (DCM/MeOH) to provide 3a10.
Step 11:
[0233] To 3a10 (995.0 mg, 3.03 mmol) in DMSO (30.00 mL) and MeOH
(15.00 mL) is added TEA (2.22 mL, 15.95 mmol), followed by
Pd(dppf)Cl.sub.2 DCM adduct (287.5 mg, 0.35 mmol). The resulting
solution is purged with CO(g) and heated at 85.degree. C. under 1
atmosphere of CO(g) for 8 h. The solution is cooled to RT and
diluted with DCM. The organic phase is washed with water
(3.times.), washed with brine, dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The crude material is purified
by Combiflash (DCM/MeOH) to provide 3a11.
Step 12:
[0234] 3a11 (583 mg, 1.90 mmol) is dissolved in DMSO (35.00 mL) and
cooled to 0.degree. C. 1N NaOH (aqueous) (7.60 mL, 7.60 mmol) is
added to the solution. The mixture is warmed to 45.degree. C. and
stirred for 3 h. The mixture is quenched with 1N HCl (aqueous) and
extracted with EtOAc. The organic layers are combined, washed with
brine (2.times.), dried over MgSO.sub.4, filtered and concentrated
under reduced pressure to provide 3a12 which is used as is in
subsequent reactions.
Example 4
Preparation of intermediates 4a8
##STR00015## ##STR00016##
[0235] Step 0:
[0236] 1-bromo-3-chloro-2-methylpropane (88.1 g, 514 mmol) is added
to diethyl malonate (82.4 g, 514 mmol, Aldrich). This mixture is
heated to 80.degree. C., and sodium ethoxide in EtOH (21 wt %, 383
mL, 1.03 mol) is added. The resulting solution is stirred at
80-85.degree. C. for 14 h, and then cooled to RT. The solvent is
removed in vacuo. The residue is cooled to 0.degree. C.,
neutralized with 2N HCl and extracted with diethyl ether
(3.times.200 mL). The combined organic extracts are washed with
water and a saturated aqueous solution of NaHCO.sub.3 and dried
over anhydrous Na.sub.2SO.sub.4. The solvent is vacuum distilled to
provide 4a0.
[0237] Compound 4a1 is prepared from 4a0 using a procedure
analogous to that described in Example 3, Steps 1 to 5.
Step 1:
[0238] Compound 4a1 (4.00 g, 17.83 mmol) is charged in a round
bottom flask with water (50.00 mL) and 5N NaOH (aqueous, 3.92 L
19.62 mmol), and the resulting mixture is stirred for 24 h. The
reaction is transferred to a separatory funnel, and washed with
ether (2.times.). The aqueous layer is transferred back to the
original flask, cooled to 0.degree. C. and quenched with 1
equivalent of HCl (aqueous) until the pH is slightly acidic (4-5).
The mixture is stirred at 0.degree. C. for 25 min to afford 4a2
which is used as such in the next step.
Step 2:
[0239] To a solution of 4a2 (3.50 g, 17.83 mmol) in water (80 mL)
at 0.degree. C. is added a solution of 4-bromobenzenediazonium
tetrafluoroborate (4.83 g, 17.83 mmol) in water (80 mL) over a
period of 15-20 min. The resulting mixture is stirred at 0.degree.
C. for 10 min, and then allowed to stir at RT for 30 min. The
reaction mixture is filtered and the residue is washed with water.
The residue is dissolved in EtOAc, washed with brine, dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
provide 4a3.
Step 3:
[0240] 4a3 (5.97 g, 17.81 mmol) is suspended in MeCN (100.0 mL) and
an aqueous solution of 1.8M sulfuric acid (30.00 mL, 540.00 mmol)
is added. The reaction mixture is stirred for 4 h at 80.degree. C.
The reaction mixture is cooled to RT, extracted with EtOAc, washed
with saturated ammonium bicarbonate (2.times.), washed with brine,
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The residue is triturated with ether for 1 h, and then
filtered. The residue is purified by Combiflash (Chloroform/MeOH)
to provide 4a4.
Step 4:
[0241] 4a4 (1.00 g, 3.14 mmol) and ethyl formate (0.616 mL, 8.02
mmol) in THF (30.00 mL) is added to NaH (60% in oil, 402.25 mg,
10.06 mmol) at 0.degree. C. The reaction mixture is stirred for 10
min at 0.degree. C., warmed to RT and stirred for 2 h. EtOAc and 1N
HCl are added and the phases are separated. The organic layer is
washed with water and brine, dried over MgSO.sub.4, filtered and
concentrated to give 4a5.
Step 5:
[0242] 4a5 (1.09 g, 3.14 mmol) is dissolved in EtOH (30.00 mL) and
hydrazine hydrate (6.00 mL, 192.64 mmol) is added. The reaction
mixture is stirred at 90.degree. C. for 2 h. EtOAc and 1N HCl are
added and the phases are separated. The organic layer is washed
with water and brine, dried over MgSO.sub.4, filtered, concentrated
under vacuum and purified by Combiflash (DCM/MeOH) to provide
4a6.
Step 6:
[0243] To a solution of 4a6 (1.07 g, 3.13 mmol) in DMSO (30.00 mL)
and MeOH (15.00 mL) is added TEA (2.29 mL, 16.45 mmol), followed by
Pd(dppf)Cl.sub.2 DCM adduct (296.4 mg, 0.36 mmol). The resulting
solution is purged with CO(g) and heated at 85.degree. C. under 1
atmosphere of CO(g) for 8 h. The solution is cooled to RT and
diluted with DCM. The organic phase is washed with water
(3.times.), washed with brine, dried over MgSO.sub.4, filtered,
concentrated under reduced pressure and purified by Combiflash
(DCM/MeOH) to provide 4a7.
Step 7:
[0244] 4a7 (110 mg, 0.34 mmol) is dissolved in DMSO (4.50 mL) and
cooled to 0.degree. C. 1N NaOH (1.37 mL, 1.37 mmol) is added to the
solution. The mixture is warmed to 45.degree. C. and stirred for 3
h. The mixture is quenched with 1N HCl and extracted with EtOAc.
The organic layers are combined, washed with brine (2.times.),
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to provide 4a8 which is used as is in subsequent
reactions.
Example 5
Preparation of Compound 2008
##STR00017##
[0246] 5a0 is made analogously to the procedure described in
Example 1, Step 1-3 using 4-bromo-aniline as the partner in Step
2.
Step 1:
[0247] To a solution of 5a0 (100.0 mg, 0.34 mmol) in THF (3.00 mL)
is added acetic anhydride (49 .mu.L, 0.52 mmol). The reaction
mixture is cooled to 0.degree. C. and 1.0M LiHMDS in THF (2.05 mL,
2.05 mmol) is added. The reaction mixture is allowed to reach RT,
and is then stirred for 1 h. The reaction mixture is warmed to RT,
and then 3 more equivalents of 1.0M LiHMDS in THF is added. The
reaction mixture is stirred for 2 h, diluted with EtOAc, quenched
with 1N HCl, extracted and the layers are separated. The aqueous
layer is extracted with EtOAc (2.times.). The organic layers are
combined, washed with brine (2.times.), dried over MgSO.sub.4,
filtered, concentrated under reduced pressure and purified by
Combiflash (Hex/EtOAc) to provide 5a1.
Step 2:
[0248] 5a1 (28.9 mg, 0.086 mmol) is dissolved in EtOH (4.5 mL) and
hydrazine hydrate (1.00 mL, 32.11 mmol) is added. The reaction
mixture is stirred at 90.degree. C. for 2 h. EtOAc and 1N HCl are
added, and the layers are separated. The organic layer is washed
with water and brine, dried over MgSO.sub.4, filtered, concentrated
under reduced pressure and purified by Combiflash (Hex/EtOAc) to
provide 5a2.
Step 3:
[0249] To a solution of 5a2 (23.6 mg, 0.071 mmol) in DMF (4.00 mL)
is added TEA (199.2 .mu.L, 1.43 mmol), and 2-(aminomethyl)pyridine
(36.8 .mu.L, 0.357 mmol). The mixture is degassed with argon for 5
min, then Pd(dppf)Cl.sub.2 DCM adduct (11.7 mg, 0.014 mmol) is
added. The reaction mixture is bubbled with CO(g) for 5 min. The
reaction mixture is kept under a CO(g) atmosphere (balloon), and
heated to 85.degree. C. for 18 h. The reaction mixture is cooled to
RT, and then EtOAc is added. The mixture is washed with water,
washed with brine (2.times.), dried over MgSO.sub.4, filtered,
concentrated under reduced pressure and purified by preparative
RP-HPLC to provide 2008.
Example 6
Preparation of Intermediate 6a2
##STR00018##
[0250] Step 1:
[0251] A mixture of 1a3 (100.0 mg, 0.39 mmol) and cupric bromide
(173.6 mg, 0.78 mmol) in EtOAc (3.00 mL) is stirred for 10 h at
reflux under a nitrogen atmosphere. The reaction mixture is cooled
to RT and filtered. The organic layer is transferred to a
separatory funnel and washed with brine, dried over MgSO.sub.4,
filtered and concentrated under reduced pressure to provide 6a1
which is taken to the next step as is.
Step 2: To a solution of 6a1 (125.0 mg, 0.37 mmol) in DMF (10.00
mL) is added thiourea (292.3 mg, 3.84 mmol). The reaction mixture
is stirred at 90.degree. C. for 3 h, then cooled to RT and diluted
with EtOAc. The mixture is washed with water (2.times.), washed
with brine (2.times.), dried over MgSO.sub.4, filtered and
concentrated under reduced pressure to afford 6a2 which is used as
is in subsequent reactions.
Example 7
Preparation of Intermediate 7a1
##STR00019##
[0253] To a solution of 6a1 (125.0 mg, 0.37 mmol) in DMF (10.00 mL)
is added thioacetamide (83.8 mg, 1.11 mmol). The reaction mixture
is stirred at 90.degree. C. for 16 h, then diluted with EtOAc. The
mixture is washed with water (2.times.), washed with brine
(2.times.), dried over MgSO.sub.4, filtered and concentrated under
reduced pressure to provide 7a1.
Example 8
Preparation of Intermediate 8a10
##STR00020## ##STR00021##
[0254] Step 1:
[0255] To a solution of indole (Aldrich, 50 g, 0.72 mol) in
anhydrous THF (800 mL) is added NaH (60% in oil, 18.7 g, 0.47 mol)
at 0.degree. C. The reaction mixture is stirred at this temperature
for 30 min, and then benzenesulfonyl chloride (82.9 g, 0.47 mol) is
added. The reaction mixture is allowed to warm to RT and is stirred
at RT overnight. The reaction mixture is quenched with water (100
mL), then extracted with EtOAc (2.times.), washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. Purification by Combiflash
(5%-10% EtOAc/Hex) affords 8a1.
Step 2:
[0256] To a solution of 8a1 (52.1 g, 0.20 mol) in anhydrous THF
(1.5 L) at -78.degree. C. is added a solution of t-BuLi (1.7M in
pentane, 157 mL). The resulting solution is stirred at -78.degree.
C. for 1 h and then a solution of 3-methyl-2-butenal (25.4 mL) in
anhydrous THF (350 mL) is added over a period of 30 min. The
reaction mixture is stirred at -78.degree. C. for 45 min. After
warming to RT, the reaction mixture is quenched by saturated
NH.sub.4Cl (.about.1.5 L), and extracted with EtOAc. The combined
organic layers are washed with brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo to provide crude 8a2 that is used as
such.
Step 3:
[0257] To a solution of the crude 8a2 obtained in step 2 in DCM
anhydrous (2 L) at RT is added 4-methyl morpholine N-oxide (35.5 g,
0.30 mol) and 4 .ANG. molecular sieves powder (59 g). After 20 min,
TPAP (3.5 g, 0.01 mol) is added and the reaction mixture is stirred
at RT overnight. The reaction mixture is filtered through a Celite
pad with DCM washings. The filtrate is concentrated and purified by
Combiflash (DCM/Hex) to provide 8a3.
Step 4:
[0258] To a solution of 8a3 (9.1 g, 26.81 mmol) in toluene
anhydrous (300 mL) is added BF.sub.3.OEt.sub.2. The resulting
mixture is heated to 120.degree. C. and stirred at this temperature
overnight. The reaction mixture is diluted with EtOAc, washed with
brine, dried over Na.sub.2SO.sub.4 and filtered though a Celite
pad. The filtrate is concentrated and purified by Combiflash
(EtOAc/Hex) to provide 8a4.
Step 5:
[0259] A 5M NaOH aqueous solution (80 mL) is added to 8a4 (6.7 g,
0.02 mol) in MeOH (670 mL). The reaction mixture is heated to
80.degree. C. and is maintained at this temperature for 90 min. The
reaction mixture is concentrated and the residue is treated with
DCM and water. The aqueous phase is back-extracted. The combined
organic phases are washed with water and brine, dried over
Na.sub.2SO.sub.4, and concentrated to provide 8a5.
Step 6:
[0260] To a solution of 8a5 (3.7 g, 18.57 mmol) in anhydrous DCM
(80 mL) at -78.degree. C. over 20 min is added pyridine (4.51 mL,
55.71 mmol) and a solution of bromine (2.86 mL, 55.71 mmol) in DCM
(5 mL). The mixture is stirred at -78.degree. C. for 3 min, then
stirred at RT under an argon atmosphere for 60 min. The reaction
mixture is cooled to -78.degree. C., then Zn (6.07 g, 92.85 mmol)
and HAc/THF (5.3 mL, 95.85 mmol) are added. The mixture is warmed
to RT over 45 min, then stirred at RT for 30 min. DCM (200 mL) is
added, and then 0.5N HCl (300 mL) is added to the mixture. The
aqueous layer is extracted (2.times.) and the combined organic
layers are concentrated and purified by Combiflash (5%-20%
EtOAc/Hex) to provide 8a6.
Step 7:
[0261] To 8a6 (500 mg, 1.80 mmol) and ethyl formate (234 .mu.L,
2.92 mmol) in THF (10.00 mL) is added NaH (60% in oil, 153.0 mg,
3.83 mmol) at 0.degree. C. The resulting mixture is stirred for 10
min at 0.degree. C., warmed to RT and stirred for 2 h. EtOAc and 1N
HCl are added and the phases are separated. The organic layer is
washed with water and brine, dried over MgSO.sub.4, filtered and
concentrated under reduced pressure to give 8a7.
Step 8:
[0262] 8a7 (365.0 mg, 1.19 mmol) is dissolved in EtOH (15.00 mL)
and hydrazine hydrate (0.111 mL, 3.58 mmol) is added. The reaction
mixture is stirred at 90.degree. C. for 2 h. EtOAc and 1N HCl are
added. The phases are separated, and the organic layer is washed
with water and brine, dried over MgSO.sub.4, filtered, concentrated
under reduced pressure and purified by Combiflash (DCM/MeOH) to
provide 8a8.
Step 9:
[0263] To a solution of 8a8 (70.0 mg, 0.23 mmol) in DMF (4.00 mL)
is added TEA (645.8 .mu.L, 4.63 mmol) and
(+/-)-3-amino-1-N--BOC-pyrrolidine (215.7 mg, 1.16 mmol,
Chembridge). The mixture is degassed with Argon for 5 min, then
Pd(dppf)Cl.sub.2 DCM adduct (37.8 mg, 0.046 mmol) is added. The
reaction mixture is bubbled with CO(g) for 5 min. The reaction
mixture is kept under a CO(g) atmosphere (balloon), and heated to
85.degree. C. for 18 h. The reaction mixture is cooled to RT, and
then EtOAc is added. The mixture is washed with water, washed with
brine (2.times.), dried over MgSO.sub.4, filtered, concentrated
under reduced pressure and purified by Combiflash (DCM/MeOH) to
provide 8a9.
Step 10:
[0264] 8a9 (48.8 mg, 0.11 mmol) is dissolved in DCM (1.00 mL) and
TFA (0.50 mL, 6.49 mmol) is added. The reaction mixture is stirred
at RT for 1 h, and then concentrated under reduced pressure,
azeotroped twice with MeOH and dried under high vacuum for 1 h to
afford 8a10 which is used as is in subsequent reactions.
Example 9
Preparation of Intermediate 9a4
##STR00022##
[0265] Step 1:
[0266] A solution of 1a5 (1.00 g, 2.55 mmol) in THF (15 mL) is
cooled to 0.degree. C. and then ethyl formate (0.5 mL, 6.15 mmol)
is added followed by the addition of NaH (60% in oil, 306 mg, 7.65
mmol). The ice bath is removed and the resulting solution is
stirred for 5 h at RT. The reaction mixture is diluted with EtOAc,
and then washed with 1M HCl, water and brine. The organic layer is
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The residue is purified by Combiflash (90:10 Hex/EtOAc)
to provide 9a1.
Step 2:
[0267] A mixture of 9a1 (555 mg, 1.28 mmol), guanidine
hydrochloride (183 mg, 1.91 mmol) and sodium carbonate (170 mg,
1.60 mmol) in 3-pentanol (10 mL) is heated overnight at 100.degree.
C. The reaction mixture is diluted with EtOAc, and then washed with
an aqueous solution of saturated NaHCO.sub.3, water and brine. The
organic layer is dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. The residue is dried under vacuum to afford
9a2 which is used in the next step without any further
purification.
Step 3:
[0268] A solution of 9a2 (584 mg, 1.28 mmol) in DCM (5 mL) is
treated with TFA (2.5 mL). The resulting solution is stirred for 4
days at RT. The solvent is evaporated in vacuo and the residue is
purified by Combiflash (EtOAc) to provide 9a3.
Step 4:
[0269] To a solution of 9a3 (116 mg, 0.34 mmol), in THF:H.sub.2O
(2.5/1, 3.5 mL), and MeOH (1 mL) is added 1M NaOH (0.86 mL, 0.86
mmol). The reaction mixture is stirred overnight at RT and then is
stirred for 3 h at 50.degree. C. The solvents are removed in vacuo.
The residue is dissolved in DMSO, filtered and purified by
preparative RP-HPLC chromatography to provide 9a4.
Example 10
Preparation of Intermediate 10a3
##STR00023##
[0270] Step 1:
[0271] A solution of 1a4 (0.97 g, 3.57 mmol), in THF (15 mL) is
cooled to 0.degree. C., and then ethyl formate (0.73 mL, 8.98 mmol)
is added, followed by the addition of NaH (60% in oil, 429 mg,
10.71 mmol). The ice bath is removed and the resulting solution is
stirred for 5 h at RT. The reaction mixture is diluted with EtOAc,
washed with 1M HCl, water and brine. The organic layer is dried
over MgSO.sub.4, filtered, concentrated under reduced pressure and
purified by Combiflash (90:10 Hex/EtOAc) to provide 10a1.
Step 2:
[0272] A mixture of 10a1 (200 mg, 0.64 mmol), acetamidine
hydrochloride (185 mg, 1.96 mmol) and sodium carbonate (172 mg,
1.62 mmol) in 3-pentanol (5 mL) is heated overnight at 100.degree.
C. The reaction mixture is diluted with EtOAc and washed with an
aqueous solution of saturated NaHCO.sub.3, water and brine. The
organic layer is dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. The residue is dried under vacuum to
provide 10a2.
Step 3:
[0273] To a solution of compound 10a2 (214 mg, 0.63 mmol) in
THF:H2O (2.5/1, 3.5 mL) and MeOH (3 mL) is added 1M NaOH (1.60 mL,
1.60 mmol). The reaction mixture is stirred for 36 h at RT. The
solvents are removed in vacuo. The reaction mixture is diluted with
1M HCl and extracted with EtOAc (2.times.). The organic layer is
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure 10a3.
Example 11
Preparation of Intermediate 11a11
##STR00024## ##STR00025##
[0274] Step 1:
[0275] Diethylamine (17.9 mL, 171 mmol) is added to a stirred
solution of acetic acid (20 mL, 356 mmol) at 0.degree. C.
Formaldehyde (37% in water, 12.6 mL, 171 mmol) and methyl
indole-5-carboxylate (25 g, 142 mmol) are then added. The resulting
mixture is stirred at RT for 2 h. The reaction mixture is
partitioned between DCM and 10% NaOH solution (60 mL). The organic
layer is separated, washed with water, dried with sodium sulphate
and concentrated to dryness to afford 11a1.
Step 2:
[0276] 11a1 (34 g, 130 mmol) is dissolved in THF (250 mL). Methyl
iodide (9.8 mL, 156 mmol) is added at 0.degree. C. and the
resulting mixture is stirred overnight at RT. A solution of KCN
(10.2 g, 156 mmol) in water (25 mL) is added, and then the reaction
mixture is refluxed for 6 h. The solvent is removed under reduced
pressure, and the residue is extracted with EtOAc. The extracts are
washed with water then brine and dried over sodium sulphate. The
organic layer is concentrated to provide 11a2.
Step 3:
[0277] A solution of 11a2 (18 g, 84 mmol) in DCM (180 mL) is
treated with 4-(dimethylamino)pyridine (0.51 g, 4.2 mmol) and
di-tert-butyldicarbonate (18.9 mL, 88 mmol). The mixture is stirred
at RT for 2 h, and then concentrated to dryness to provide
11a3.
Step 4:
[0278] To a stirred solution of 11a3 (42 g, 133 mmol) and methyl
iodide (24.9 mL, 400 mmol) in a mixture of DMF (420 mL) and THF
(270 mL) is added NaH (60% in oil, 13.4 g, 334 mmol) over a period
of 30 min at 0.degree. C. The resulting mixture is stirred at RT
for 2 h. The mixture is poured into 0.5N HCl (cold, 900 mL), and
then further diluted with water (500 mL). The aqueous layer is
extracted with EtOAc and the organic layer is washed with water,
brine and dried over Na.sub.2SO.sub.4. The solvent is evaporated
under reduced pressure to provide 11a4.
Step 5:
[0279] Platinum oxide (4 g, 16.8 mmol) is added to a stirred
solution of 11a4 (15 g, 43 mmol) in a mixture of chloroform (18
mL), THF (93 mL) and MeOH (280 mL). The reaction mixture is
maintained at 60 psi of hydrogen under a Parr-hydrogen apparatus
for 16 h. The reaction mixture is filtered through Celite and
concentrated. The residue is treated with a 0.5N NaOH solution and
extracted with DCM. The organic layer is washed with water and
brine, dried over Na.sub.2SO.sub.4 and concentrated to provide
11a5.
Step 6:
[0280] TFA (60 mL) is added at 0.degree. C. to a stirred solution
of 11a5 (15 g, 43 mmol) in DCM (120 mL). The resulting mixture is
stirred at RT overnight. The reaction mixture is concentrated and
10% KOH (aqueous) is added until the pH is basic. The reaction
mixture is then extracted with EtOAc and the organic layer is dried
over sodium sulphate and concentrated to dryness to provide
11a6.
Step 7:
[0281] TEA (7.9 mL, 56 mmol) is added to a stirred solution of 11a6
(10 g, 40 mmol) in DCM. This solution is cooled to 0.degree. C. and
phenyl chloroformate (5.65 mL, 44 mmol) is added. The resulting
mixture is stirred at RT for 1 h. The reaction mixture is diluted
with DCM and quenched with 1N HCl. The layers are separated and the
organic layer is washed with water, dried over Na.sub.2SO.sub.4 and
concentrated to provide 11a7.
Step 8:
[0282] Boron trifluoride etherate (3.4 mL, 26 mmol) is added to a
stirred solution of 11a7 (8.5 g, 23 mmol) in toluene (150 mL). The
reaction mixture is refluxed for 3 h then allowed to cool to RT.
Water (200 mL) and a saturated NaHCO.sub.3 (aqueous) solution (200
mL) are added to the reaction. The resulting mixture is stirred at
RT for 1 hr. The resulting solid is filtered and dried under vacuum
to provide 11a8.
Step 9:
[0283] A mixture of 11a8 (1.0 g, 3.7 mmol) and phosphorus
pentasulfide (1.6 g, 3.7 mmol) in anhydrous pyridine (10 mL) is
refluxed overnight. The solvent is removed in vacuo and the
residual material is triturated twice with a mixture of MeOH and
MeCN to provide 11a9.
Step 10:
[0284] A mixture of 11a9 (250.0 mg, 0.87 mmol), aminoacetaldehyde
diethylacetal (138.1 .mu.L, 0.95 mmol) and p-toluenesulfonic acid
(181.4 mg, 0.95 mmol) in butanol (10 mL) is heated under reflux for
overnight. p-toluenesulfonic acid (181.4 mg, 0.95 mmol) is added to
the mixture which is then heated under reflux for 2 days. The
butanol is evaporated (azeotrope with Hex) and ice water (100 mL)
is added. The solution is basified with 1N NaOH, then extracted
with EtOAc, dried over MgSO.sub.4, filtered and concentrated. The
crude mixture is purified by Combiflash (50% EtOAc/Hex to 100%
EtOAc) to provide 11a10.
Step 11:
[0285] To a solution of 11a10 (39.0 mg, 0.13 mmol) in MeOH (1.0 mL)
and THF (0.5 mL) is added 1N NaOH (0.4 mL) and the mixture is
stirred at RT for 2 h. The reaction is continued overnight at
reflux. The mixture is concentrated, diluted with water and
acidified with 1N HCl until the pH is about 4. The solution is
extracted with EtOAc (2.times.). The organic layers are combined,
washed with brine, dried over MgSO.sub.4, filtered and concentrated
to provide 11a11.
Example 12
Preparation of Intermediate 12a2
##STR00026##
[0286] Step 1:
[0287] A mixture of 11a9 (100.0 mg, 0.35 mmol) and formic hydrazine
(25.0 mg, 0.42 mmol, Aldrich) in cyclohexanol (1.0 mL) is heated at
reflux overnight under a nitrogen atmosphere. Formic hydrazine
(50.0 mg, 0.84 mmol) is added to the mixture that is then stirred
at reflux for 16 h. Formic acid (50.0 mg, 0.84 mmol) is added and
the reaction mixture is stirred for 2 days at 160.degree. C. The
mixture is cooled to RT and then triturated with EtOAc (2.times.)
to provide 12a1.
Step 2:
[0288] To a solution of 12a1 (30.6 mg, 0.1 mmol) in DMSO (1.0 mL)
is added 1N NaOH (0.52 mL, 0.52 mmol). The mixture is stirred at RT
overnight. 1N NaOH (0.2 mL, 0.2 mmol) is added to the mixture which
is then stirred for 2 h. The reaction mixture is acidified with 1N
HCl (.about.0.5 mL) and extracted with EtOAc (3.times.). The
combined organic extracts are combined, washed with brine, dried
over MgSO.sub.4, filtered and concentrated to provide 12a2.
Example 13
General Method A
Preparation of Intermediate 13a2
[0289] Example 13 is an example of a general method wherein the
carboxylic partners, such as 2a4, are coupled with the appropriate
Boc-protected partner, such as 13a0, followed by deprotection.
##STR00027##
Step 1:
[0290] To a solution of 2a4 (200 mg, 0.71 mmol) and 13a0 (198.6 mg,
1.07 mmol, Chembridge) in DMF (5 mL) are added HATU (406.0 mg, 1.07
mmol) and TEA (0.2 mL, 1.42 mmol). The reaction mixture is stirred
for 1 h at RT, quenched with AcOH (0.1 mL) and EtOAc and water are
added. The layers are separated and the aqueous phase is extracted
with EtOAc. The organic layers are combined, washed with brine,
dried over MgSO.sub.4, filtered and concentrated to provide
13a1.
Step 2:
[0291] 13a1 (319.1 mg, 0.71 mmol) is dissolved in a 4N HCl solution
of dioxane (2.0 mL, 0.5 mmol) and the solution is stirred for 30
min. The mixture is concentrated and purified by Combiflash (100%
DCM to 10% MeOH/DCM) to provide 13a2.
[0292] Intermediates 13b2 to 13g2 are made analogously to the
procedure described in Example 13.
##STR00028##
Example 14
General Method B
Preparation of Compound 1015
[0293] Example 14 is an example of a general method wherein the
intermediate (13a2 to 13i2) obtained in Example 13 (GENERAL METHOD
A) is coupled with the suitable carboxylic acid partner.
##STR00029##
[0294] To a solution of 13a2 (40.0 mg, 0.11 mmol) and 14a1 (12.7
mg, 0.10 mmol, Aldrich) in DMF (1.0 mL) are added HATU (49.4 mg,
0.11 mmol) and TEA (35.9 .mu.L, 0.26 mmol). The reaction mixture is
stirred for 4 h at RT, quenched with AcOH (0.2 mL) and the
resulting solution is purified by preparative RP-HPLC to provide
compound 1015.
Example 15
Preparation of Compound 1006
##STR00030##
[0296] To a solution of 2a4 (45.0 mg, 0.16 mmol) and 15a1 (39.5 mg,
0.32 mmol, Small-Molecule) in DMF (1 mL) are added HATU (91.3 mg,
0.24 mmol) and TEA (66.9 .mu.L, 0.48 mmol). The reaction mixture is
stirred for 1 h at RT, quenched with AcOH (0.1 mL) and purified by
preparative RP-HPLC to provide compound 1006.
Example 16
Preparation of Compound 1126
##STR00031##
[0298] 2a4 (50.0 mg, 0.18 mmol) and 16a1 (20.1 mg, 0.21 mmol,
Aldrich) are dissolved in anhydrous pyridine (1.0 mL). The solution
is cooled to -15.degree. C. and phosphorus oxychloride (24.9 .mu.L,
0.26 mmol) is added under stirring. The reaction mixture is stirred
at -15.degree. C. for 30 min and then is stirred at RT overnight.
Phosphorus oxychloride (24.9 .mu.L, 0.26 mmol) is added to the
reaction mixture which is then stirred for 3 h at RT. The reaction
mixture is quenched with 1N HCl (0.5 mL) and extracted with DCM
using a phase-separator. The solvents are evaporated and the
residue is purified by preparative RP-HPLC to provide compound
1126.
Example 17
Preparation of Compound 1117
##STR00032##
[0300] A solution of 13a2 (20.0 mg, 0.06 mmol), 17a1 (6.3 .mu.L,
0.07 mmol, Aldrich) and TEA (48.0 .mu.L, 0.34 mmol) in THF (1.0 mL)
is stirred overnight at RT. The reaction mixture is quenched with
TFA (0.1 mL) and the resulting solution is concentrated in vacuo.
The crude mixture is purified by preparative RP-HPLC to provide
compound 1117.
Example 18
Preparation of Compound 1118
##STR00033##
[0302] A solution of 13a2 (20.0 mg, 0.06 mmol), isopropyl
isocyanate (6.8 .mu.L, 0.07 mmol, Aldrich) and TEA (48.0 .mu.L,
0.34 mmol) in THF (1.0 mL) is stirred overnight at RT. The reaction
mixture is quenched with TFA (0.1 mL) and the resulting solution is
concentrated in vacuo. The crude mixture is purified by preparative
RP-HPLC to provide compound 1118.
Example 19
Preparation of Intermediate 19a1
##STR00034##
[0304] To a solution of 2a2 (175 mg, 0.41 mmol) in DMF (2 mL) is
added NaH (60% in oil, 49 mg, 1.22 mmol) at 0.degree. C.
Iodomethane (30.2 .mu.l, 0.49 mmol) is added and the reaction
mixture is stirred at RT for 16 h. 5M NaOH (0.24 mL, 1.22 mmol) and
DMSO (1 mL) are added. The reaction mixture is stirred at RT for 3
h, and then diluted with EtOAc and 1M HCl. The layers are separated
and the organic layer is washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated. The residue is dissolved in TFA
(2 mL) and triflic anhydride (40 .mu.L) is added. The mixture is
stirred at RT for 1 h, then concentrated and purified by Combiflash
(0:100 to 5:95, MeOH/DCM) to provide 19a1.
Example 20
Preparation of Compound 2020
##STR00035##
[0306] 2a4 (36 mg, 0.12 mmol) in ether/MeOH (1:1, 5 mL) is treated
with TMS-diazomethane (2.0M, 2.5 mL). The resulting solution is
stirred for 1 h at RT. The solvents are evaporated in vacuo. The
residue is dissolved in DMSO, filtered and purified by preparative
RP-HPLC to provide compound 2020.
Example 21
Preparation of Compound 1124
##STR00036##
[0307] Step 1:
[0308] To a solution 2a4 (35 mg, 0.12 mmol) and HATU (52 mg, 0.14
mmol) in DMSO (0.5 mL) is added a solution of
tetrahydrothiopyran-4-ylamine (18 mg, 0.15 mmol, Frontier) and TEA
(0.087 mL, 0.62 mmol) in DMSO (1.5 mL). The resulting solution is
stirred overnight at RT. The reaction mixture is then diluted with
EtOAc and washed with an aqueous solution of saturated NaHCO.sub.3,
H.sub.2O (2.times.) and brine. The organic layers are combined,
dried over MgSO.sub.4, filtered and concentrated to provide
21a1.
Step 2:
[0309] To 21a1 (44 mg, 0.11 mmol), in MeOH (3 mL) is added a
solution of oxone (107 mg, 0.17 mmol) in H.sub.2O (1.5 mL). The
resulting suspension is stirred for 2 h at RT. The solvent is
evaporated in vacuo. The residue is dissolved in DMSO, filtered and
then purified by preparative RP-HPLC to provide compound 1124.
Example 22
Preparation of Intermediate 22a2
##STR00037##
[0311] 3a12 is coupled with 13a0 (step 1), followed by deprotection
(step 2) using a procedure analogous to that described in Example
13 to provide intermediate 22a2.
Example 23
Preparation of Compound 5001
##STR00038##
[0313] 8a8 is coupled with 23a1 (Aldrich) using a procedure
analogous to that described in Step 9 of Example 8 to provide
compound 5001.
Example 24
Preparation of Intermediate 24a2
##STR00039##
[0315] 9a4 is coupled with 13a0 (step 1), followed by deprotection
(step 2) using a procedure analogous to that described in Example
13 to provide intermediate 24a2.
Example 25
Preparation of Intermediate 25a2
##STR00040##
[0316] Step 1:
[0317] TEA (849 mL, 6.1 mmol), HATU (1.85 g, 4.88 mmol) and 25a0
(832 mg, 4.47 mmol, Aldrich) are added to a solution of 25a01 (500
mg, 4.1 mmol, Aldrich) in DMSO (5 mL). The reaction mixture is
stirred for 1 h at RT, quenched with a saturated solution of
NH.sub.4Cl (aqueous) and EtOAc and water are added. The layers are
separated and the aqueous phase is extracted with EtOAc. The
organic layers are combined, washed with brine, dried over
MgSO.sub.4, filtered and concentrated to provide 25a1.
Step 2:
[0318] 25a1 (443 mg, 1.52 mmol) is dissolved in a 4N HCl solution
of dioxane (10.0 mL, 40 mmol) and MeOH (2 mL). The resulting
solution is stirred for 30 min and then concentrated to provide
25a2.
Example 26
Preparation of Intermediate 26a2
##STR00041##
[0320] 26a0 (TCI-US) is coupled with 26a01 (Anichem) (step 1),
followed by deprotection (step 2) using a procedure analogous to
that described in Example 25 to provide intermediate 26a2.
Example 27
Preparation of Compound 2001
##STR00042##
[0322] 12a2 is coupled with 23a1 using a procedure analogous to
that described in Example 15 to provide compound 2001.
Example 28
Preparation of Compound 1011
##STR00043##
[0324] TEA (67 .mu.L, 0.48 mmol) and HATU (91 mg, 0.24 mmol) are
added to a solution of ammonium bicarbonate (10.9 mg, 0.64 mmol)
and 2a4 (45.0 mg, 0.16 mmol) in DMF (1 mL). The reaction mixture is
stirred for 1 h at RT, filtered and purified by preparative RP-HPLC
to provide compound 1011.
Example 29
Preparation of Compound 2012
##STR00044##
[0326] 11a11 is coupled with 29a1 (Oakwood) using a procedure
analogous to that described in Example 15 to provide compound
2012.
Example 30
Preparation of Compound 3011
##STR00045##
[0328] 3a12 is coupled with 30a1 (Princeton) using a procedure
analogous to that described in Example 15 to provide compound
3011.
Example 31
Preparation of Compound 2018
##STR00046##
[0330] 7a1 is coupled with 31a1 (Intermed) using a procedure
analogous to that described in Example 15 to provide compound
2018.
Example 32
Preparation of Compound 2004
##STR00047##
[0332] 19a1 is coupled with 23a1 (Aldrich) using a procedure
analogous to that described in Example 15 to provide compound
2004.
Example 33
Preparation of Compound 2028
##STR00048##
[0334] 10a3 is coupled with 31a1 using a procedure analogous to
that described in Example 15 to provide compound 2028.
Example 34
Preparation of Compound 2014
##STR00049##
[0336] 6a2 is coupled with 31a1 using a procedure analogous to that
described in Example 15 to provide compound 2014.
Example 35
Preparation of Compound 2022
##STR00050##
[0338] 9a4 is coupled with 23a1 using a procedure analogous to that
described in Example 15 to provide compound 2022.
Example 36
Preparation of Compound 3018
##STR00051##
[0340] 22a2 is coupled with 14a1 using a procedure analogous to
that described in Example 14 to afford compound 3018.
Example 37
Preparation of Compound 4004
##STR00052##
[0342] 4a8 is coupled with 23a1 using a procedure analogous to that
described in Example 15 to provide compound 4004.
Example 38
Preparation of Compound 2027
##STR00053##
[0344] 24a2 is coupled with 38a1 (Aldrich) using a procedure
analogous to that described in Example 14 to afford compound
2027.
Example 39
Preparation of Compound 2015
##STR00054##
[0346] 6a2 is coupled with 25a2 using a procedure analogous to that
described in Example 15 to provide compound 2015.
Example 40
Preparation of Compound 2019
##STR00055##
[0348] 7a1 is coupled with 25a2 using a procedure analogous to that
described in Example 15 to provide compound 2019.
Example 41
Preparation of Compound 5002
##STR00056##
[0350] 38a1 is coupled with 8a10 using a procedure analogous to
that described in Example 14 to afford compound 5002.
Example 42
Preparation of Compound 2002
##STR00057##
[0352] 19a1 is coupled with 25a2 using a procedure analogous to
that described in Example 15 to provide compound 2002.
Example 43
Preparation of Compound 4001
##STR00058##
[0354] 4a8 is coupled with 25a2 using a procedure analogous to that
described in Example 15 to provide compound 4001.
Example 44
Preparation of Compound 4002
##STR00059##
[0356] 4a8 is coupled with 26a2 using a procedure analogous to that
described in Example 15 to provide compound 4002.
Example 45
Preparation of Compound 2029
##STR00060##
[0358] EDCI (150 mg, 0.78 mmol) is added to a solution of 45a1 (27
mg, 0.2 mmol, TCI-US) and 2a4 (50 mg, 0.18 mmol) in DMF (2 mL). The
reaction mixture is stirred at RT for 18 h, quenched with AcOH (0.2
mL) and purified by RP-HPLC to provide compound 2029.
Example 46
[0359] Production of HCV pseudoparticles (HCVpp) and VSV
pseudoparticles (VSVpp) Functional HCVpp are produced in 293FT
cells (Invitrogen, Cat. No. R700-07) by co-transfection of HCV
E1/E2 expression construct (pE1E2Con1#3) and a non-replicating
HIV-1 based reporter vector (pNL4.3LucE-R-.DELTA.725). The
pNL4.3LucE-R-.DELTA.725 reporter vector is generated by deleting a
725 pb DNA fragment within the gp160 encoding sequence
corresponding to the StuI/BsaI restriction fragment of the original
reporter vector (pNL4.3LucE-R-: NIH AIDS Research & Reference
Reagent Program, Cat. No. 3418). The pE1E2Con1#3 expression vector
encodes the HCV envelope gene (residues 171-746) (HCV isolate Con1,
accession number AJ238799) cloned (HindIII/XbaI) into the pcDNA.TM.
3.1/Hygro.sup.(+) expression vector (Invitrogen Cat. No. V870-20).
For HCVpp production, 293FT cells are co-transfected with
pNL4.3LucE-R-.DELTA.725 reporter vector and pE1/E2Con1#3 expression
vector in a 30:1 (.mu.g:.mu.g) ratio using Lipofectamine.TM. 2000
(Invitrogen Cat. No. 11668-027) in serum-free Opti-MEM.RTM.I medium
(Invitrogen Cat. No. 31985-070). Six hours post-transfection, the
transfection medium is replaced with DMEM medium (Invitrogen, Cat.
No. 319-005-CL) supplemented with 3% FBS (HyClone, Cat. No.
SH30396.03) and 0.1 mM NEAA (Invitrogen, Cat. No. 11140-050). Cell
culture supernatants containing HCVpp are collected at 48 hours
post-transfection and centrifuged at 1000.times.g for 10 min to
remove cellular debris. HEPES buffer (1M, pH7.5, Invitrogen Cat.
No. 15630-080) is added at a final concentration of 10 mM to the
clarified viral HCVpp containing supernatants, aliquoted and stored
at -80.degree. C. VSV pseudoparticles (VSVpp) for evaluating
specificity of the compounds are generated according to the above
transfection protocol using a pLP-VSVG (Invitrogen, Cat. No.
K4975-00) expression vector encoding the G envelope gene of VSV
rather than the pE1E2Con1#3 expression vector.
Infection with HCV Pseudoparticles (HCVpp)
[0360] HCVpp incorporating a lentiviral backbone harboring the
luciferase gene are used to assay for HCV entry as follows.
Hep3B2.1-7 (ATCC number HB-8064) cells seeded in 96-well plates
(Black 96-well ViewPlate.TM., Packard Cat. No. 6005182) are
incubated with a concentration range of the tested compounds and
supernatent containing HCVpp and polybrene. Typically the different
reagents are mixed as follows: 10 .mu.L of cells (1.times.10.sup.6
cells/mL in DMEM medium supplemented with 3% FBS and 0.1 mM NEAA),
15 .mu.L of compound solution (DMEM medium supplemented with 3%
FBS, 0.1 mM NEAA and 3% DMSO) and 50 .mu.L of undiluted supernatant
containing HCVpp to which a solution of polybrene is added
(Sequa-brene, Sigma Cat. No. S2667, final concentration of 4.5
mg/mL). The plates are centrifuged for 60 min at 400.times.g and
then incubated for 4 h at 37.degree. C. (5% CO.sub.2) before
addition of 10 .mu.L of DMEM medium supplemented with 20% FBS and
0.1 mM NEAA. Seventy-two hours after infection the luciferase level
is evaluated by a standard luminescences assay. Compounds that
reduce viral entry limit the amount of HCVpp that is transduced
into the host cells and thus reduce the luciferase levels and the
resulting luminescence signal. The most efficacious compounds
induce the most significant reduction in luminescence.
[0361] Specificity of the compounds is tested by evaluating the
inhibitory effect on VSVpp according to the infection protocol
described above for HCVpp, except that supernatant containing VSVpp
is diluted in media to generate a similar signal as generated using
the supernatant containing undiluted HCVpp. Compounds that inhibit
HCVpp entry significantly more (10-fold) than infections mediated
by VSVpp are considered to be specific. All the compounds listed in
Tables 1 and 5 are found to significantly reduce viral entry as
measured by the HCVpp/luciferase assay, and are specific when
assayed against the inhibitory effect on VSVpp.
[0362] The compounds of the invention show EC.sub.50 values in the
range of 2.5 .mu.M or less in the assay of Example 46.
Representative data is shown below:
TABLE-US-00003 EC.sub.50 (nM) Cmpd # Example 46 1006 112 1011 72
1015 12 1126 65 1118 19 2001 1395 2004 109 2012 230 2014 280 2018
320 2020 97 2022 1350 2028 885 3011 2.8 3018 6.7 4004 54 5002
59
Tables of Compounds
[0363] The following tables list compounds representative of the
invention. All of the compounds in Tables 1 to 5 are synthesized
analogously to the Examples described above. It will be apparent to
a skilled person that the analogous synthetic routes may be used,
with appropriate modifications, to prepare the compounds of the
invention as described herein.
[0364] Retention times (t.sub.R) for each compound are measured
using the standard analytical HPLC or UPLC conditions described in
the Examples. As is well known to one skilled in the art, retention
time values are sensitive to the specific measurement conditions.
Therefore, even if identical conditions of solvent, flow rate,
linear gradient, and the like are used, the retention time values
may vary when measured, for example, on different HPLC or UPLC
instruments. Even when measured on the same instrument, the values
may vary when measured, for example, using different individual
HPLC or UPLC columns, or, when measured on the same instrument and
the same individual column, the values may vary, for example,
between individual measurements taken on different occasions.
TABLE-US-00004 TABLE 1 ##STR00061## t.sub.R Cmpd # R.sup.4 (min) (M
+ H).sup.+ Ex. # 1001 ##STR00062## 1.51 455.3 13a2 & Ex. 14
1002 ##STR00063## 1.4 399.2 Ex. 15 1003 ##STR00064## 1.55 372.2 Ex.
15 1004 ##STR00065## 1.53 413.3 Ex. 15 1005 ##STR00066## 1.35 387.3
Ex. 15 1006 ##STR00067## 1.49 351.4 Ex. 15 1007 ##STR00068## 1.51
387.3 Ex. 15 1008 ##STR00069## 1.39 377.3 Ex. 15 1009 ##STR00070##
1.53 365.4 Ex. 15 1010 CH.sub.3 1.42 295.3 Ex. 15 1011 H 1.31 281.2
Ex. 28 1012 ##STR00071## 1.56 445.3 13a2 & Ex. 14 1013
##STR00072## 1.51 470.3 13a2 & Ex. 14 1014 ##STR00073## 1.47
455.3 13a2 & Ex. 14 1015 ##STR00074## 1.55 455.3 13a2 & Ex.
14 1016 ##STR00075## 1.58 469.3 13e2 & Ex. 14 1017 ##STR00076##
1.59 475.3 13e2 & Ex. 14 1018 ##STR00077## 1.56 458.3 13e2
& Ex. 14 1019 ##STR00078## 1.62 473.3 13e2 & Ex. 14 1020
##STR00079## 1.63 473.3 13e2 & Ex. 14 1021 ##STR00080## 1.61
459.3 13e2 & Ex. 14 1022 ##STR00081## 1.46 474.3 13e2 & Ex.
14 1023 ##STR00082## 1.5 459.3 13e2 & Ex. 14 1024 ##STR00083##
1.55 459.3 13e2 & Ex. 14 1025 ##STR00084## 1.55 547.3 13e2
& Ex. 14 1026 ##STR00085## 1.5 472.3 13e2 & Ex. 14 1027
##STR00086## 1.61 469.3 13c2 & Ex. 14 1028 ##STR00087## 1.67
483.3 13c2 & Ex. 14 1029 ##STR00088## 1.63 475.2 13c2 & Ex.
14 1030 ##STR00089## 1.6 458.3 13c2 & Ex. 14 1031 ##STR00090##
1.68 473.3 13c2 & Ex. 14 1032 ##STR00091## 1.67 473.3 13c2
& Ex. 14 1033 ##STR00092## 1.64 459.3 13c2 & Ex. 14 1034
##STR00093## 1.54 459.3 13c2 & Ex. 14 1035 ##STR00094## 1.61
459.3 13c2 & Ex. 14 1036 ##STR00095## 1.58 547.3 13c2 & Ex.
14 1037 ##STR00096## 1.55 472.3 13c2 & Ex. 14 1038 ##STR00097##
1.51 474.3 13c2 & Ex. 14 1039 ##STR00098## 1.35 394.3 Ex. 15
1040 ##STR00099## 1.58 459.3 13b2 & Ex. 14 1041 ##STR00100##
1.55 441.2 13b2 & Ex. 14 1042 ##STR00101## 1.62 455.3 13b2
& Ex. 14 1043 ##STR00102## 1.53 430.2 13b2 & Ex. 14 1044
##STR00103## 1.62 445.3 13b2 & Ex. 14 1045 ##STR00104## 1.52
445.2 13b2 & Ex. 14 1046 ##STR00105## 1.48 431.2 13b2 & Ex.
14 1047 ##STR00106## 1.64 459.3 13b2 & Ex. 14 1048 ##STR00107##
1.64 458.3 13b2 & Ex. 14 1049 ##STR00108## 1.63 444.3 13b2
& Ex. 14 1050 ##STR00109## 1.52 519.3 13b2 & Ex. 14 1051
##STR00110## 1.62 443.3 13h2 & Ex. 14 1052 ##STR00111## 1.5
418.2 13h2 & Ex. 14 1053 ##STR00112## 1.56 432.3 13h2 & Ex.
14 1054 ##STR00113## 1.64 433.3 13h2 & Ex. 14 1055 ##STR00114##
1.51 430.2 13h2 & Ex. 14 1056 ##STR00115## 1.44 419.3 13h2
& Ex. 14 1057 ##STR00116## 1.72 483.3 13h2 & Ex. 14 1058
##STR00117## 1.64 470.3 13a2 & Ex. 14 1059 ##STR00118## 1.67
472.3 13a2 & Ex. 14 1060 ##STR00119## 1.59 456.3 13a2 & Ex.
14 1061 ##STR00120## 1.54 444.3 13a2 & Ex. 14 1062 ##STR00121##
1.55 448.3 13a2 & Ex. 14 1063 ##STR00122## 1.61 459.2 13a2
& Ex. 14 1064 ##STR00123## 1.5 444.3 13a2 & Ex. 14 1065
##STR00124## 1.49 459.3 13a2 & Ex. 14 1066 ##STR00125## 1.58
512.3 13a2 & Ex. 14 1067 ##STR00126## 1.51 456.3 13a2 & Ex.
14 1068 ##STR00127## 1.54 459.3 13a2 & Ex. 14 1069 ##STR00128##
1.53 495.3 13a2 & Ex. 14 1070 ##STR00129## 1.67 487.3 13a2
& Ex. 14 1071 ##STR00130## 1.52 445.3 13a2 & Ex. 14 1072
##STR00131## 1.6 458.3 13a2 & Ex. 14 1073 ##STR00132## 1.6
458.3 13a2 & Ex. 14 1074 ##STR00133## 1.61 458.3 13a2 & Ex.
14 1075 ##STR00134## 1.44 470.3 13a2 & Ex. 14 1076 ##STR00135##
1.57 533.3 13a2 & Ex. 14 1077 ##STR00136## 1.52 533.3 13a2
& Ex. 14 1078 ##STR00137## 1.51 456.3 13a2 & Ex. 14 1079
##STR00138## 1.47 470.3 13a2 & Ex. 14 1080 ##STR00139## 1.47
471.3 13a2 & Ex. 14 1081 ##STR00140## 1.65 461.2 13a2 & Ex.
14 1082 ##STR00141## 1.46 459.3 13a2 & Ex. 14 1083 ##STR00142##
1.55 477.2 13a2 & Ex. 14 1084 ##STR00143## 2.14 469.4 13g2
& Ex. 14 1085 ##STR00144## 2.24 483.4 13g2 & Ex. 14 1086
##STR00145## 2.21 468.4 13g2 & Ex. 14 1087 ##STR00146## 2.08
459.3 13g2 & Ex. 14 1088 ##STR00147## 1.5 440.3 Ex. 15 1089
##STR00148## 1.25 375.3 Ex. 15 1090 ##STR00149## 1.99 399.3 Ex. 15
1091 ##STR00150## 1.22 352.3 Ex. 15 1092 ##STR00151## 1.6 386.3 Ex.
15 1093 ##STR00152## 1.19 350.3 Ex. 15 1094 ##STR00153## 1.46 364.3
Ex. 15 1095 ##STR00154## 1.31 392.3 Ex. 15 1096 ##STR00155## 1.73
393.3 Ex. 15 1097 ##STR00156## 1.67 365.3 Ex. 15 1098 ##STR00157##
1.5 390.3 Ex. 15 1099 ##STR00158## 1.65 442.2 Ex. 15 1100
##STR00159## 1.57 416.2 Ex. 15 1101 ##STR00160## 1.52 390.3 Ex. 15
1102 ##STR00161## 1.58 415.2 Ex. 15 1103 ##STR00162## 1.65 483.3
13e2 & Ex. 14 1104 ##STR00163## 1.43 446.3 13b2 & Ex. 14
1105 ##STR00164## 1.52 418.2 13h2 & Ex. 14 1106 ##STR00165##
1.61 469.3 13a2 & Ex. 14 1107 ##STR00166## 1.52 470.3 13a2
& Ex. 14 1108 ##STR00167## 1.46 444.2 13a2 & Ex. 14 1109
##STR00168## 1.38 424.3 Ex. 15 1110 ##STR00169## 1.15 350.3 Ex. 13
(13a2) 1111 ##STR00170## 1.28 396.3 Ex. 15 1112 ##STR00171## 1.23
378.3 Ex. 15 1113 ##STR00172## 1.64 383.2 Ex. 15 1114 ##STR00173##
1.5 337 Ex. 15 1115 ##STR00174## 1.4 415.1 Ex. 15 1116 ##STR00175##
1.44 413.2 Ex. 15 1117 ##STR00176## 1.6 421.1 Ex. 17 1118
##STR00177## 1.61 435.2. Ex. 18 1119 ##STR00178## 473.3 473.3 13i2
& Ex. 14 1120 ##STR00179## 2.13 473.2 13f2 & Ex. 14 1121
##STR00180## 1.55 339.1 Ex. 15 1122 ##STR00181## 1.68 323.1 Ex.
15
1123 ##STR00182## 1.29 366.2 Ex. 15 1124 ##STR00183## 1.94 413.1
Ex. 21 1125 ##STR00184## 1.63 375.1 Ex. 16 1126 ##STR00185## 1.66
358.1 Ex. 16 1127 ##STR00186## 2.15 483.2 13d2 & Ex. 14 1128
##STR00187## 2.25 497.2 13d2 & Ex. 14 1129 ##STR00188## 2.14
484.2 13d2 & Ex. 14 1130 ##STR00189## 2.04 473.2 13d2 & Ex.
14
TABLE-US-00005 TABLE 2 ##STR00190## Cmpd # R.sup.A Y.sup.1/Y.sup.2
t.sub.R (min) (M + H).sup.+ Ex. # 2001 ##STR00191## ##STR00192##
1.28 373.3 Ex. 27 2002 ##STR00193## ##STR00194## 1.63 469.3 Ex. 42
2003 ##STR00195## ##STR00196## 1.59 413.2 Ex. 32 2004 ##STR00197##
##STR00198## 1.72 386.2 Ex. 32 2005 ##STR00199## ##STR00200## 1.00
282.2 Ex. 2 (2a4) 2006 ##STR00201## ##STR00202## 1.59 384.3 Ex. 15
2007 ##STR00203## ##STR00204## 1.17 399.1 Ex. 29 2008 ##STR00205##
##STR00206## 1.72 386.3 Ex. 5 2009 ##STR00207## ##STR00208## 1.45
413.2 Ex.15 2010 ##STR00209## ##STR00210## 1.45 399.1 Ex. 15 2011
##STR00211## ##STR00212## 1.27 372.1 Ex. 29 2012 ##STR00213##
##STR00214## 1.26 365.2 Ex. 29 2013 ##STR00215## ##STR00216## 1.63
404.1 Ex. 34 2014 ##STR00217## ##STR00218## 1.5 431.1 Ex. 34 2015
##STR00219## ##STR00220## 1.56 487.1 Ex. 39 2016 ##STR00221##
##STR00222## 1.58 386.2 Ex. 15 2017 ##STR00223## ##STR00224## 1.86
403.1 Ex. 31 2018 ##STR00225## ##STR00226## 1.76 430.1 Ex. 31 2019
##STR00227## ##STR00228## 1.79 486.2 Ex. 40 2020 ##STR00229##
##STR00230## 2.59 296 Ex. 20 2021 ##STR00231## ##STR00232## 1.67
426 Ex. 35 2022 ##STR00233## ##STR00234## 1.91 399.1 Ex. 35 2023
##STR00235## ##STR00236## 2.27 398.1 Ex. 33 2024 ##STR00237##
##STR00238## 1.82 482.2 Ex. 38 2025 ##STR00239## ##STR00240## 1.94
496.1 Ex. 38 2026 ##STR00241## ##STR00242## 1.63 487.1 Ex. 38 2027
##STR00243## ##STR00244## 1.72 472.2 Ex. 38 2028 ##STR00245##
##STR00246## 1.53 425 Ex. 33 2029 ##STR00247## ##STR00248## 1.84
363.3 Ex. 45
TABLE-US-00006 TABLE 3 ##STR00249## Cmpd # R.sup.4 t.sub.R (min) (M
+ H).sup.+ Ex. # 3001 ##STR00250## 1.5 390.3 Ex. 30 3002
##STR00251## 1.4 457.3 Ex. 36 3003 ##STR00252## 1.53 467.3 Ex. 36
3004 ##STR00253## 1.62 384.2 Ex. 30 3005 ##STR00254## 1.48 411.2
Ex. 30 3006 ##STR00255## 1.57 441.3 Ex. 30 3007 ##STR00256## 1.63
399.3 Ex. 30 3008 ##STR00257## 1.64 456.3 Ex. 30 3009 ##STR00258##
1.65 377.2 Ex. 30 3010 ##STR00259## 1.7 377.1 Ex. 30 3011
##STR00260## 1.61 427.1 Ex. 30 3012 ##STR00261## 1.59 428.1 Ex. 30
3013 ##STR00262## 1.57 425.1 Ex. 30 3014 ##STR00263## 1.56 404.3
Ex. 36 3015 ##STR00264## 1.63 460.4 Ex. 36 3016 ##STR00265## 1.49
471.4 Ex. 36 3017 ##STR00266## 1.64 470.4 Ex. 36 3018 ##STR00267##
1.64 467.3 Ex. 36 3019 ##STR00268## 1.63 481.1 Ex. 36 3020
##STR00269## 1.57 545.2 Ex. 36 3021 ##STR00270## 1.6 468 Ex. 36
TABLE-US-00007 TABLE 4 ##STR00271## Cmpd # R.sup.4 t.sub.R (min) (M
+ H).sup.+ Ex. # 4001 ##STR00272## 1.67 481.3 Ex. 43 4002
##STR00273## 1.62 471.2 Ex. 44 4003 ##STR00274## 1.63 425.2 Ex. 37
4004 ##STR00275## 1.76 398.3 Ex. 37
TABLE-US-00008 TABLE 5 Cmpd # Structure t.sub.R (min) (M + H).sup.+
Ex. # 5001 ##STR00276## 1.49 358.2 Ex. 23 5002 ##STR00277## 1.33
431.2 Ex. 41 5003 ##STR00278## 1.38 441.3 Ex. 41
[0365] Each reference, including all patents, patent applications,
and publications cited in the present application is incorporated
herein by reference in its entirety, as if each of them is
individually incorporated. Further, it would be appreciated that,
in the above teaching of invention, the skilled in the art could
make certain changes or modifications to the invention, and these
equivalents would still be within the scope of the invention
defined by the appended claims of the application.
* * * * *